Modulators of serotonin receptors

ABSTRACT

Certain biphenyl compounds are serotonin modulators useful in the treatment of serotonin-mediated diseases.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. provisional patentapplication Ser. No. 61/109,899, filed Oct. 30, 2008.

FIELD OF THE INVENTION

There is provided by the present invention compounds that are serotoninreceptor modulators. More particularly, there is provided by the presentinvention biphenyl compounds that are serotonin receptor modulatorsuseful for the treatment of disease states mediated by serotoninreceptor activity.

BACKGROUND OF THE INVENTION

Serotonin (5-hydroxytryptamine, 5-HT) is a major neurotransmittereliciting effects via a multiplicity of receptors. To date, at leastfifteen different 5-HT receptors have been identified, largely as theresult of cDNA cloning. These receptors have been grouped into sevenfamilies (5-HT₁ through 5-HT₇) (Hoyer, D. et al. Pharmacol. Biochem.Behav. 2002, 71, 533-554).

Fourteen of the fifteen cloned 5-HT receptors are expressed in thebrain. 5-HT is implicated in many disease states, particularlyconditions of the central nervous system including; depression, anxiety,schizophrenia, eating disorders, obsessive compulsive disorder, learningand memory dysfunction, migraine, chronic pain, sensory perception,motor activity, temperature regulation, nociception, sexual behavior,hormone secretion, and cognition.

The identification of multiple 5-HT receptors has provided theopportunity to characterize existing therapeutic agents thought to actvia the serotonergic system. Consequently, this has led to therealization that many drugs have non-selective properties (Roth, B. L.et al. Neuroscientist 2000, 6(4), 252-262). For example, theantipsychotic drugs, clozapine, chlorpromazine, haloperidol andolanzapine exhibit affinities for multiple serotonin receptors inaddition to other families of receptors. Similar behavior has been notedfor antidepressants including imipramine, nortriptaline, fluoxetine andsertraline. Similarly, the anti-migraine agent sumatriptan exhibits highaffinity for several serotonin receptors. While the lack of selectivityoften contributes to a favorable therapeutic outcome, it can also causeundesirable and dose-limiting side effects (Stahl, S. M. EssentialPsychopharmacology, 2^(nd) ed., Cambridge University Press, Cambridge,U.K., 2000). For example, the inhibition of serotonin and norepinephrineuptake together with 5-HT₂ receptor blockade is responsible for thetherapeutic effects of the tricyclic antidepressants. In contrast, theirblockade of histamine H₁, muscarinic and alpha-adrenergic receptors canlead to sedation, blurred vision and orthostatic hypertensionrespectively. Likewise, the atypical antipsychotics, includingolanzapine and clozapine, are considered to have positive therapeuticeffects attributable to their actions at 5-HT₂, D₂ and 5-HT₇ receptors.Conversely, their side effect liability is due to their affinities for arange of dopaminergic, serotonergic and adrenergic receptors.

Elucidating selective ligands has the potential to ameliorate untowardpharmacologies and provide novel efficacious therapies. Moreimportantly, the ability to obtain compounds which portray receptorselectivity provides the prospect to target distinct therapeuticmechanisms and improve clinical responses with a single drug.Consequently, there remains a need for potent serotonin receptormodulators with desirable pharmaceutical properties.

SUMMARY OF THE INVENTION

Certain biphenyl derivatives have now been found to have 5HT₇ modulatingactivity. In particular, the invention is directed to the general andpreferred embodiments defined, respectively, and by the independent anddependent claims appended hereto, which are incorporated by referenceherein.

Thus, in one general aspect, the invention relates to compounds ofFormulae (I) and (II):

whereinR¹ is —H, —C₁₋₄alkyl, or —C₃₋₆cycloalkyl;m is 1 or 2,n is 1 or 2, with the proviso that if m is 2, then n is not 1;L is absent or O;R² is —H, halo, —CN, —CF₃, —OC₀₋₄alkylCF₃, —OC₁₋₄alkyl,—C₃₋₆cycloalkoxy, —OCH₂C₃₋₆cycloalkyl, or —C(O)N(R_(a))₂;

each R_(a) is individually —H or —C₁₋₄alkyl;

R³ is —H or —C₁₋₄alkyl;o is 0, 1, or 2; andeach R⁴ substituent is independently —H, halo, —OCF₃, —CF₃, —CN,—C₁₋₄alkyl, or —OC₁₋₄alkyl.

The invention also relates to stereoisomeric forms, hydrates, solvates,pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs,and pharmaceutically active metabolites of compounds of Formulae (I) or(II). In certain preferred embodiments, the compound of Formulae (I) or(II) is a compound selected from those species described or exemplifiedin the detailed description below.

In a further general aspect, the invention relates to pharmaceuticalcompositions each comprising: (a) an effective amount of an agentselected from compounds of Formulae (I) or (II) and stereoisomericforms, hydrates, solvates, pharmaceutically acceptable salts,pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites thereof; and (b) a pharmaceutically acceptable excipient.

In another general aspect, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or medical condition (collectively, “indications”) mediated by 5HT₇activity, comprising administering to the subject in need of suchtreatment an effective amount of a compound of Formulae (I) or (II), ora stereoisomeric form, hydrate, solvate, pharmaceutically acceptablesalt, pharmaceutically acceptable prodrug, or pharmaceutically activemetabolite of such compound. In certain preferred embodiments of theinventive method, the disease, disorder, or medical condition isselected from: cognitive disorders, sleep disorders, psychiatricdisorders, and other disorders.

Preferred embodiments, features, and advantages of the invention will beapparent from the following detailed description and through practice ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION AND ITS PREFERRED EMBODIMENTS

The invention may be more fully appreciated by reference to thefollowing detailed description, including the following glossary ofterms and the concluding examples. For the sake of brevity, thedisclosures of the publications, including patents, cited in thisspecification are herein incorporated by reference.

The terms “including”, “containing” and “comprising” are used herein intheir open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which may also be structurally depicted by a bond,“I”), ethyl (Et), n-propyl (Pr), isopropyl (iPr), butyl (nBu), isobutyl(iBu), sec-butyl (sBu), tert-butyl (tBu), pentyl, isopentyl,tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinaryskill in the art and the teachings provided herein would be consideredequivalent to any one of the foregoing examples.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities (depicted without their bonds ofattachment):

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Illustrative examples (depictedwithout their bonds of attachment) include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities (depicted without their bonds of attachment):

Those skilled in the art will recognize that the species of cycloalkyl,heterocycloalkyl, and heteroaryl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formulae as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. It is understood that some compounds referred toherein are chiral and/or have geometric isomeric centers, for example E-and Z-isomers. All optical isomers and stereoisomers of the compounds ofany general structural formula, and mixtures thereof, are consideredwithin the scope of the formulae. Thus, any general formula given hereinis intended to represent a racemate, one or more enantiomeric forms, oneor more diastereomeric forms, one or more atropisomeric forms, andmixtures thereof. Furthermore, certain structures may exist as geometricisomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.Additionally, any general formula given herein is intended to embracehydrates, solvates, and polymorphs of such compounds, and mixturesthereof. Furthermore, certain compounds referred to herein can exist insolvated as well as unsolvated forms. It is understood that thisinvention encompasses all such solvated and unsolvated forms thatpossess the activity that characterizes the compounds of this invention.

In another example, a zwitterionic compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Any general formula given herein is also intended to represent unlabeledforms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures of the formulas givenherein except that one or more atoms are replaced by an atom having aselected atomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labeled compoundsare useful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques(such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly preferredfor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

When referring to a formula given herein, the selection of a particularmoiety from a list of possible species for a specified variable is notintended to define the moiety for the variable appearing elsewhere. Inother words, where a variable appears more than once in a formula, thechoice of the species from a specified list is independent of the choiceof the species for the same variable elsewhere in the formula unlessotherwise indicated.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², A, X⁴, X⁵, X⁶, X⁷, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g),R^(h), R^(i), R^(j), R^(k), R^(l), R^(m), and R^(o), and any othergeneric substituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², A, X⁴, X⁵, X⁶, X⁷, R^(a), R^(h), R^(c), R^(d), R^(e), R^(f), R^(g),R^(h), R^(i), R^(j), R^(k), R^(l), R^(m), and R^(o), and any othergeneric substituent symbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n. Any disubstituent referred to herein is meantto encompass the various attachment possibilities when more than one ofsuch possibilities are allowed. For example, reference to disubstituent-A-B—, where A≠B, refers herein to such disubstituent with A attached toa first substituted member and B attached to a second substitutedmember, and it also refers to such disubstituent with A attached to thesecond substituted member and B attached to the first substitutedmember.

The compounds of Formulae (I) and (II) and their pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, andpharmaceutically active metabolites of the present invention are usefulas serotonin receptor modulators in the methods of the invention.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formulae (I) or (II),that is non-toxic, biologically tolerable, or otherwise biologicallysuitable for administration to the subject. See, generally, G. S.Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient SaltSelection based on Analysis of the Orange Book Database”, J. Med. Chem.,2007, 50:6665-72, S. M. Berge, et al., “Pharmaceutical Salts”, J PharmSci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties,Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich,2002. Examples of pharmaceutically acceptable salts are those that arepharmacologically effective and suitable for contact with the tissues ofpatients without undue toxicity, irritation, or allergic response. Acompound of Formulae (I) or (II) may possess a sufficiently acidicgroup, a sufficiently basic group, or both types of functional groups,and accordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

When the compound of Formulae (I) or (II) contains a basic nitrogen, thedesired pharmaceutically acceptable salt may be prepared by any suitablemethod available in the art, for example, treatment of the free basewith an inorganic acid, such as hydrochloric acid, hydrobromic acid,sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid,and the like, or with an organic acid, such as acetic acid, phenylaceticacid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleicacid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formulae (I) or (II) is an acid, such as acarboxylic acid or sulfonic acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal hydroxide,alkaline earth metal hydroxide, any compatible mixture of bases such asthose given as examples herein, and any other base and mixture thereofthat are regarded as equivalents or acceptable substitutes in light ofthe ordinary level of skill in this technology. Illustrative examples ofsuitable salts include organic salts derived from amino acids, such asN-methyl-D-glucamine, lysine, choline, glycine and arginine, ammonia,carbonates, bicarbonates, primary, secondary, and tertiary amines, andcyclic amines, such as tromethamine, benzylamines, pyrrolidines,piperidine, morpholine, and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum, and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formulae (I) or (II), and treatment methods employingsuch pharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formulae (I) or (II). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to thesubject. Illustrative procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

Exemplary prodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formulae (I)or (II). Examples of amino acid residues include the twenty naturallyoccurring amino acids, commonly designated by three letter symbols, aswell as 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formulae (I) or (II)as amides or alkyl esters. Representative pharmaceutically acceptableamides of the invention include those derived from ammonia, primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondary aminesinclude 5- or 6-membered heterocyclic or heteroaromatic ring moietiescontaining at least one nitrogen atom and optionally between 1 and 2additional heteroatoms. Preferred amides are derived from ammonia,C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Representativepharmaceutically acceptable esters of the invention include C₁₋₇alkyl,C₅₋₇cycloalkyl, phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred estersinclude methyl esters. Prodrugs may also be prepared by derivatizingfree hydroxy groups using groups including hemisuccinates, phosphateesters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls,following procedures such as those outlined in Fleisher et al., Adv.Drug Delivery Rev. 1996, 19, 115-130. Carbamate derivatives of hydroxyand amino groups may also yield prodrugs. Carbonate derivatives,sulfonate esters, and sulfate esters of hydroxy groups may also provideprodrugs. Derivatization of hydroxy groups as (acyloxy)methyl and(acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester,optionally substituted with one or more ether, amine, or carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, is also useful to yield prodrugs. Prodrugs of this typemay be prepared as described in Robinson et al., J Med. Chem. 1996, 39(1), 10-18. Free amines can also be derivatized as amides, sulfonamidesor phosphonamides. All of these prodrug moieties may incorporate groupsincluding ether, amine, and carboxylic acid functionalities.

The present invention also relates to pharmaceutically activemetabolites of the compounds of Formulae (I) or (II), which may also beused in the methods of the invention. A “pharmaceutically activemetabolite” means a pharmacologically active product of metabolism inthe body of a compound of Formulae (I) or (II) or salt thereof. Prodrugsand active metabolites of a compound may be determined using routinetechniques known or available in the art. See, e.g., Bertolini, et al.,J Med. Chem. 1997, 40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv DrugRes. 1984, 13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press,1985); and Larsen, Design and Application of Prodrugs, Drug Design andDevelopment (Krogsgaard-Larsen, et al., eds., Harwood AcademicPublishers, 1991).

The compounds of Formulae (I) or (II) and their pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, andpharmaceutically active metabolites of the present invention are usefulas modulators of the seratonin receptor in the methods of the invention.As such modulators, the compounds may act as antagonists, agonists, orinverse agonists. The term “modulators” include both inhibitors andactivators, where “inhibitors” refer to compounds that decrease,prevent, inactivate, desensitize or down-regulate seratonin receptorexpression or activity, and “activators” are compounds that increase,activate, facilitate, sensitize, or up-regulate seratonin receptorexpression or activity. Many of the compounds of the present inventionare 5-HT₇ modulators that act as 5-HT₇ agonists. As such, the compoundsare useful in the treatment of 5-HT₇-mediated disease in which anincrease, induction, activation or up-regulation of serotonin receptorexpression or activity is required.

The term “treat” or “treating” as used herein is intended to refer toadministration of an active agent or composition of the invention to asubject for the purpose of effecting a therapeutic or prophylacticbenefit through modulation of serotonin receptor activity. Treatingincludes reversing, ameliorating, alleviating, inhibiting the progressof, lessening the severity of, or preventing a disease, disorder, orcondition, or one or more symptoms of such disease, disorder orcondition mediated through modulation of serotonin receptor activity.The term “subject” refers to a mammalian patient in need of suchtreatment, such as a human.

In treatment methods according to the invention, an effective amount ofa pharmaceutical agent according to the invention is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic or prophylactic benefitin patients in need of such treatment for the designated disease,disorder, or condition. Effective amounts or doses of the compounds ofthe present invention may be ascertained by routine methods such asmodeling, dose escalation studies or clinical trials, and by taking intoconsideration routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the compound, the severity andcourse of the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician.

The invention may be particularly useful in the treatment or preventionof diseases, disorders, or conditions mediated by serotonin receptoractivity, such as: central nervous system disorders such as sleepdisorders (including insomnia), depression/anxiety, generalized anxietydisorder, schizophrenia, bipolar disorders, cognitive disorders, mildcognitive impairment, Alzheimer's disease, Parkinson's disease,psychotic disorders, phobic disorders, obsessive-compulsive disorder,mood disorders, post-traumatic stress and other stress-relateddisorders, migraine, pain, eating disorders, obesity, sexualdysfunction, metabolic disturbances, hormonal imbalance, hot flashesassociated with menopause, alcohol abuse, drug abuse, and addictivedisorders including drug addiction and alcohol addiction. Furtherdiseases associated with serotonin receptor activity for which thecompounds may be useful for treating are nausea, inflammation, centrallymediated hypertension, sleep/wake disturbances, jetlag, and circadianrhythm abnormalities. The compounds may also be used in the treatmentand prevention of hypotension, peripheral vascular disorders,cardiovascular shock, renal disorders, gastric motility, diarrhea,spastic colon, irritable bowel disorders, ischemias, septic shock,urinary incontinence and other disorders related to the gastrointestinaland vascular systems. In addition, compounds of the present inventionmay be used in methods for treating or preventing a range of oculardisorders including glaucoma, optic neuritis, diabetic retinopathy,retinal edema, and age-related macular degeneration. Symptoms or diseasestates are intended to be included within the scope of “medicalconditions, disorders, or diseases.”

The compounds of the present invention are 5-HT₇ modulators, many ofwhich are 5-HT₇ agonists. As such, the compounds are useful in thetreatment of 5-HT₇ mediated disease states. Where the compounds possesssubstantial 5-HT₇ modulating activity, they may be particularly usefulin methods for treating depression/anxiety, sleep/wake disturbances,sleep disorders, jet lag, migraine, urinary incontinence, gastricmotility, and irritable bowel disorders, hypertension, analgesic, andirritable bowel syndrome.

Particularly, as serotonin receptor modulators, the compounds of thepresent invention are useful in the treatment or prevention ofdepression, anxiety, sleep disorders, and circadian rhythmabnormalities.

The compounds of the invention are used, alone or in combination withone or more other active ingredients, to formulate pharmaceuticalcompositions of the invention. In addition, the compounds of theinvention may be used in combination with additional active ingredientsin the treatment of the above conditions. In an exemplary embodiment,additional active ingredients are those that are known or discovered tobe effective in the treatment of conditions, disorders, or diseasesmediated by serotonin receptors or that are active against anothertarget associated with the particular condition, disorder, or disease.Suitable examples include: H₁ receptor antagonists, H₂ receptorantagonists, H₃ receptor antagonists, topiramate (TOPAMAX™), andneurotransmitter modulators such as norepinephrine reuptake inhibitors(NRIs), selective serotonin reuptake inhibitors (SSRIs), noradrenergicreuptake inhibitors, non-selective serotonin re-uptake inhibitors(NSSRIs), acetylcholinesterase inhibitors (such astetrahydroaminoacridine, Donepezil (ARICEPT™), Rivastigmine, orGalantamine (REMINYL™)), modafinil, antipsychotics, sedatives, monoamineoxidase inhibitors (MAOs), and tricyclic antidepressants (TCAs). Thecombination may serve to increase efficacy (e.g., by including in thecombination a compound potentiating the potency or effectiveness of acompound according to the invention), decrease one or more side effects,or decrease the required dose of the compound according to theinvention. In preferred embodiments, the combination method employsdoses containing additional active ingredients in the range of about 20to 300 mg per dose.

A pharmaceutical composition of the invention comprises: (a) aneffective amount of a compound of Formulae (I) and (II), or apharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically active metabolite thereof; and (b) apharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of a agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. It is anticipated that thecompounds of the invention can be administered by oral or parenteralroutes, including intravenous, intramuscular, intraperitoneal,subcutaneous, rectal and topical administration, and inhalation. Fororal administration, the compounds of the invention will generally beprovided in the form of tablets or capsules or as an aqueous solution orsuspension. Tablets for oral use may include the active ingredient mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservatives. Suitableinert diluents include sodium and calcium carbonate, sodium and calciumphosphate and lactose. Cornstarch and alginic acid are suitabledisintegrating agents. Binding agents may include starch and gelatin.The lubricating agent, if present, will generally be magnesium stearate,stearic acid or talc. If desired, the tablets may be coated with amaterial such as glyceryl monostearate or glyceryl distearate, to delayabsorption in the gastrointestinal tract.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For intramuscular, intraperitoneal, subcutaneous and intravenoususe, the compounds of the invention will generally be provided insterile aqueous solutions or suspensions, buffered to an appropriate pHand isotonicity. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Aqueous suspensions according to the inventionmay include suspending agents such as cellulose derivatives, sodiumalginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agentsuch as lecithin. Suitable preservatives for aqueous suspensions includeethyl and n-propyl p-hydroxybenzoate.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery.

Compounds of the invention may alternatively be administered in methodsof this invention by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier.

Effective doses of the compounds of the present invention may beascertained by conventional methods. The specific dosage level requiredfor any particular patient will depend on a number of factors, includingseverity of the condition being treated, the route of administration andthe weight of the patient. In general, however, it is anticipated thatthe daily dose (whether administered as a single dose or as divideddoses) will be in the range 0.01 to 1000 mg per day, more usually from 1to 500 mg per day, and most usually from 10 to 200 mg per day. Expressedas dosage per unit body weight, a typical dose will be expected to bebetween 0.0001 mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7mg/kg, and most especially between 0.15 mg/kg and 2.5 mg/kg.

The invention includes also pharmaceutically acceptable salts of thecompounds represented by Formulae (I) or (II), preferably of thosedescribed below. Pharmaceutically acceptable salts of the specificcompounds exemplified herein are especially preferred.

In certain embodiments of compounds of the invention, chemical entitiesare of the formula (I). In further embodiments of the invention,chemical entities are of the formula (II).

In certain preferred embodiments of compounds of Formulae (I) or (II), mhas the value of 1 or 2 and n has the value of 1 or 2; however, if m is2 then n is not 1. In preferred embodiments, m is 1 and n is 1. Infurther preferred embodiments, m is 1 and n is 2. In further preferredembodiments, m is 2 and n is 2. In certain embodiments, compounds are ofFormula (II) and m and n are each 1.

In certain embodiments of compounds of Formulae (I) or (II), L is eitherabsent or is an —O—. In certain embodiments of the invention, L isabsent. In further embodiments, L is —O—.

In certain embodiments of compounds of Formulae (I) or (II), R¹ is —H,—C₁₋₄alkyl, or C₃₋₆cycloalkyl. In preferred embodiments, R¹ is hydrogen,methyl, isopropyl, or cyclobutyl. In further preferred embodiments, R¹is Hydrogen.

In certain embodiments of compounds of Formulae (I) or (II), R² isselected from —H, halo, —CN, —OCF₃, —OCH₂CF₃, —OC₁₋₄alkyl,—C₃₋₆cycloalkoxy, —OCH₂C₃₋₆cycloalkyl, —C(O)N(R_(a))₂, or —C(O)R_(b)wherein each R_(a) is individually —H or —C₁₋₄alkyl and R_(b) is—C₁₋₄alkyl, —C₃₋₆cycloalkyl, or —CH₂C₃₋₆cycloalkyl. In furtherembodiments, the R² substituent is selected from —H, —Cl, —OCH₃,—OCH₂CH₃, —CN, —OCF₃, cyclobutoxy, cyclopropylmethoxy, isopropoxy, or—C(O)N(CH₂CH₃).

In certain preferred embodiments of compounds of Formulae (I) or (II),R³ is —H or —C₁₋₄alkyl. In further preferred embodiments, R³ is —H, or—CH₃.

In certain preferred embodiments of compounds of Formulae (I) or (II), ois 0, 1, or 2. In various preferred embodiments, o is 1. In furtherpreferred embodiments, o is 2.

In certain preferred embodiments of compounds of Formulae (I) or (II),each R⁴ is independently selected from —H, halo, —C₁₋₄alkyl,—C₁₋₄alkoxy, —OCF₃, —CF₃, or —CN. In further embodiments, each R⁴ isindependently selected from hydrogen, chloro, fluoro, —CH₃, —CF₃, —OCF₃,—OCH₃, and —CN.

Preferred compounds, which are biphenyls, are selected from the groupconsisting of:

Ex Chemical Name 1 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine; 23-(4′-Fluoro-4-methoxy-2′-methyl-biphenyl-3-yloxy)-azetidine; 33′-(Azetidin-3-yloxy)-4′-methoxy-biphenyl-2-carbonitriletrifluoroacetate; 43-(4-Methoxy-2′,3′-dimethyl-biphenyl-3-yloxy)-azetidine; 53-(3′-Fluoro-4-methoxy-2′-methyl-biphenyl-3-yloxy)-azetidine; 63-(4-Methoxy-2′,6′-dimethyl-biphenyl-3-yloxy)-azetidinetrifluoroacetate; 73-(4-Methoxy-2′-trifluoromethoxy-biphenyl-3-yloxy)-azetidine; 83-(4-Methoxy-2′-methyl-biphenyl-3-yloxy)-azetidine trifluoroacetate; 93-(4,2′-Dimethoxy-biphenyl-3-yloxy)-azetidine; 103-(2′-Chloro-4-methoxy-6′-trifluoromethyl-biphenyl-3-yloxy)- azetidinetrifluoroacetate; 11 3-(4-Methoxy-4′-methyl-biphenyl-3-yloxy)-azetidine;12 3-(4′-Fluoro-4-methoxy-3′-methyl-biphenyl-3-yloxy)-azetidine; 133-(4-Methoxy-3′-methyl-biphenyl-3-yloxy)-azetidine; 143-(4-Methoxy-3′,4′-dimethyl-biphenyl-3-yloxy)-azetidine; 153-(4-Methoxy-biphenyl-3-yloxy)-azetidine; 163-(4-Methoxy-2′,5′-dimethyl-biphenyl-3-yloxy)-azetidine; 173-(2′-Chloro-4-methoxy-biphenyl-3-yloxy)-azetidine; 183-(2′-Chloro-4-methoxy-biphenyl-3-yloxy)-1-isopropyl-azetidinetrifluoroacetate; 193-(2′-Chloro-4-methoxy-biphenyl-3-yloxy)-1-cyclobutyl-azetidinetrifluoroacetate; 20 3-(2′-Trifluoromethyl-biphenyl-3-yloxy)-azetidine;21 3-(2′-Chloro-biphenyl-3-yloxy)-azetidine; 223-(3′-Methyl-biphenyl-3-yloxy)-azetidine; 233-(2′-Methyl-biphenyl-3-yloxy)-azetidine; 243-(4,2′-Dichloro-biphenyl-3-yloxy)-azetidine trifluoroacetate; 253-(4-Chloro-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidinetrifluoroacetate; 26 3-(4-Chloro-2′-methyl-biphenyl-3-yloxy)-azetidinetrifluoroacetate; 27 3-(4-Chloro-3′-methyl-biphenyl-3-yloxy)-azetidinetrifluoroacetate; 283-(Azetidin-3-yloxy)-2′-trifluoromethyl-biphenyl-4-carbonitrile; 293-(Azetidin-3-yloxy)-biphenyl-4-carbonitrile; 303-(Azetidin-3-yloxy)-2′-methyl-biphenyl-4-carbonitrile; 315-(Azetidin-3-yloxy)-2-methyl-biphenyl-4-carbonitrile; 323-(4-Ethoxy-2′-methyl-biphenyl-3-yloxy)-azetidine hydrochloride; 333-[2′-Methyl-4-(2,2,2-trifluoro-ethoxy)-biphenyl-3-yloxy]-azetidine; 343-(4-Cyclobutoxy-2′-methyl-biphenyl-3-yloxy)-azetidine; 353-(4-Cyclopropylmethoxy-2′-methyl-biphenyl-3-yloxy)-azetidine; 363-(4-lsopropoxy-2′-methyl-biphenyl-3-yloxy)-azetidine; 373-(Azetidin-3-yloxy)-2′-trifluoromethyl-biphenyl-4-carboxylic aciddiethylamide; 38 3-(4-Chloro-3′-methyl-biphenyl-2-yloxy)-azetidine; 393-(4-Chloro-2′-methyl-biphenyl-2-yloxy)-azetidine; 403-(4-Chloro-3′-trifluoromethyl-biphenyl-2-yloxy)-azetidine; 413-(4-Chloro-4′-fluoro-3′-methyl-biphenyl-2-yloxy)-azetidine; 423-(4-Chloro-3′,4′-dimethyl-biphenyl-2-yloxy)-azetidine; 43(±)-3-(4-Methoxy-2′-methyl-biphenyl-3-yl)-pyrrolidine; 44(±)-3-(3′-Fluoro-4-methoxy-2′-methyl-biphenyl-3-yl)-pyrrolidine; 45(±)-3-(2′,3′-Difluoro-4-methoxy-biphenyl-3-yl)-pyrrolidine; 46(±)-3-(4-Methoxy-3′-trifluoromethyl-biphenyl-3-yl)-pyrrolidine; 47(±)-3-(4-Methoxy-2′-trifluoromethyl-biphenyl-3-yl)-pyrrolidine; 48(±)-3-(4-Methoxy-2′-trifluoromethoxy-biphenyl-3-yl)-pyrrolidine; 49(±)-3-(4-Methoxy-biphenyl-3-yl)-pyrrolidine; 50(±)-3-(4-Methoxy-biphenyl-3-yl)-1-methyl-pyrrolidine; 51(±)-3-Biphenyl-2-yl-pyrrolidine; 52(±)-3-(3′-Methyl-biphenyl-2-yl)-pyrrolidine; 53(±)-3-(4′-Methyl-biphenyl-2-yl)-pyrrolidine; 543-(4′-Chloro-biphenyl-2-yl)-pyrrolidine; 55(±)-3-(3′,4′-Dimethyl-biphenyl-2-yl)-pyrrolidine; 56(±)-3-(3′,4′-Dimethyl-biphenyl-2-yl)-1-methyl-pyrrolidine; 57(±)-3-(2′-Methyl-biphenyl-2-yl)-pyrrolidine; 58(±)-1-Methyl-3-(2′-methyl-biphenyl-2-yl)-pyrrolidine; 59(±)-3-(2′-Methoxy-biphenyl-2-yl)-pyrrolidine; 60(±)-1-Methyl-3-(4′-methyl-biphenyl-2-yl)-pyrrolidine; 61(±)-1-Methyl-3-(3′-methyl-biphenyl-2-yl)-pyrrolidine; 62(±)-3-(2′-Methoxy-5′-methyl-biphenyl-2-yl)-pyrrolidine; 63(±)-3-(2′-Methoxy-5′-methyl-biphenyl-2-yl)-1-methyl-pyrrolidine; 64(±)-3-(2′-Methoxy-biphenyl-2-yl)-1-methyl-pyrrolidine; 65(±)-3-(4,3′-Dichloro-biphenyl-2-yl)-pyrrolidine; 66(±)-3-(4-Chloro-4′-fluoro-3′-methyl-biphenyl-2-yl)-pyrrolidine; 67(±)-3-(4-Chloro-3′,4′-dimethyl-biphenyl-2-yl)-pyrrolidine; 684-(4-Methoxy-biphenyl-3-yloxy)-piperidine; and 694-(4-Methoxy-2′-trifluoromethyl-biphenyl-3-yloxy)-piperidineand stereoisomeric forms, hydrates, solvates, pharmaceuticallyacceptable salts, prodrugs, and active metabolites thereof.

Exemplary chemical entities useful in methods of the invention will nowbe described by reference to illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables in theformulas depicted in the schemes below are as defined above in referenceto Formulae (I) and (II). Reactions may be performed between the meltingpoint and the reflux temperature of the solvent, and preferably between0° C. and the reflux temperature of the solvent.

List of abbreviations: Ac=Acetyl, AIBN=azobisisobutyronitrile,Boc=tert-Butylcarbamoyl, m-CPBA=meta-chloroperoxybenzoic acid,DCE=dichloroethane, DEAD=diethyldiazodicarboxylate, DIBAL-H=diisobutylaluminum hydride, DIEA=N,N-Diisopropylethylamine,DMA=N,N-Dimethylacetamide, DME=Ethylene glycol dimethyl ether,DMF=dimethylformamide, DMSO=Dimethyl sulfoxide, Et₃N=triethylamine,Et₂O=diethyl ether, EtOAc=Ethyl acetate, MeCN=acetonitrile,MeOH=methanol, MsCl=Methanesulfonyl chloride, TFA=trifluoroacetic acid,TFAA=trifluoroacetic acid anhydride, THF=tetrahydrofuran, TLC=thin layerchromatography,Q-Phos=1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene.

The biphenyl compounds of formulas (I) and (II) may be prepared by anumber of reaction schemes. Preparation of compounds of formula (I) isdescribed in Schemes A and H. Preparation of compounds of formula (II)is described in Schemes B, C, D, E, F, and G. Persons skilled in the artmay recognize that certain compounds are more advantageously produced byone scheme as compared to the other.

Intermediates of formula A10 were prepared according to Scheme A.Compounds of formula A1 were treated with tert-butylamine in thepresence of a dehydrating agent such as SiO₂, CuSO₄, Ti(OiPr)₄, MgSO₄ ormolecular sieves in a suitable solvent such as THF, CH₂Cl₂, benzene,toluene, MeOH or EtOH. In preferred embodiments, MgSO₄ in CH₂Cl₂ wasused to give compounds of formula A2. Compounds of formula A4 wereobtained from compounds of formula A2 using compounds of formula A3 in asuitable solvent such as DMF, DMSO, NMP or THF in the presence of a basesuch as NaH, KOtBu or Cs₂CO₃, preferably NaH in DMF. Compounds offormula A5 were obtained from compounds of formula A4 upon basichydrolysis of the compound obtained from the treatment of compounds offormula A5 with an oxidant such as m-chloroperoxybenzoic acid (m-CPBA)in CH₂Cl₂. The hydrolysis is performed using a base such as NaOH or KOHin a solvent such as MeOH, EtOH or H₂O. One skilled in the art willrecognize that compounds of formula A5 can be converted into precursorsfor transition-metal catalyzed cross-coupling reactions, such as Stille,Suzuki, Negishi, Sonagashira or other such coupling reactions known toone skilled in the art. For example, treatment of compounds of theformula A5 with a triflating agent such as trifluoromethanesulfonicanhydride (Tf₂O) or N-phenyltrifluoromethanesulfonamide in DCE, CH₂Cl₂,THF or the like in the presence of a base such as pyridine,triethylamine or diisopropylethylamine provides compounds of the formulaA6. Treatment of compounds of formula A6 with organoboron compounds A7in the presence of a catalyst such as PdCl₂(dppf), PdCl₂(dppe)Pd₂(dba)₃, Pd(dba)₂, PdCl₂(PPh₃)₂, Pd(PPh₃)₄ in a solvent such as PhCH₃,1,4-dioxane, THF, DMA, DMF or DME in the presence of a base such asNa₂CO₃, K₂CO₃, Cs₂CO₃, CsF, KF, K₃PO₄, KOAc or the like and a ligandtypically used in such reactions such as Q-Phos, dppf, dppe or PPh₃ andthe like affords compounds of formula A8 at temperatures ranging from rtto 160° C. using conventional or microwave heating.

The amine in compounds of formula A8 may be protected, as indicated byP¹, as an alkyl or benzyl amine, amide, carbamate or other groups suchas described in “Protecting Groups in Organic Synthesis”, 3^(rd) ed.; T.W. Greene and P. G. Wuts, John Wiley and Sons, 1999. Preferably, P¹ is—C₁₋₆Alkyl, —COOC₁₋₆Alkyl, —(C═O)C₁₋₆Alkyl, benzyl substituted orunsubstituted with —OC₁₋₆Alkyl or C₁₋₆Alkyl, or benzhydryl substitutedor unsubstituted with —OC₁₋₆Alkyl or C₁₋₆Alkyl). A further preferredprotecting group is t-butyl carbamate (Boc) or trifluoroacetamide. Thisprotecting group (P¹) on the nitrogen may be removed using generallyaccepted methods or may be converted directly into compounds of theformula A10. More specifically a group such as a Boc group may beremoved with an acid such as trifluoroacetic acid or hydrochloric acidand the like in a solvent such as CH₂Cl₂, EtOAc, THF, 1,4-dioxane, MeOHor EtOH. A group such as trifluoroacetamide was removed using a basesuch as NH₃, NH₄OH or K₂CO₃ in an alcoholic solvent such as MeOH or EtOHand the like.

It will be generally recognized that compounds of the formula A9represent a subset of compounds of formula A10 where R¹ is equal to H.Compounds of formula A9 or A10 may be converted to their correspondingsalts using methods generally accepted to those skilled in the art.

Compounds such as A10 were prepared from compounds of the formula A9using methods such as reductive amination or alkylation. Thus treatmentof A9 with a compound of formula an aldehyde or ketone in the presenceof a reductant such as NaBH₄, NaBH₃CN, NaBH(OAc)₃ or hydrogen gas in thepresence of a catalyst in a solvent such as CH₂Cl₂, THF, DCE, MeOH, EtOHor similar afforded compounds of formula A10. One skilled in the artwill recognize that the addition of acid to decrease the pH of thereaction mixture to less than pH 7 may be required. Examples of acidsmay include AcOH, Ti(O-iPr)₄, trifluoroacetic acid or hydrochloric acidand the like. One skilled in the art will also recognize that compoundsof formula A10 may be obtained from A9 upon treatment with an alkylchloride, bromide, iodide, mesylate or tosylate and the like in asolvent such as DMF, DMA, THF or EtOH in the presence of bases such asNaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃.

Intermediates of formula B5 were prepared according to Scheme B.Compounds of the formula B1 were prepared similar to compounds offormula A5 (Scheme 1). Compounds of the formula B2 were obtained fromcompounds of the formula B1 upon treatment with methyl iodide in asolvent such as DMF, DMA, THF or EtOH in the presence of bases such asNaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃. One skilled in the art will recognizethat compounds of formula B2 can be utilized for transition-metalcatalyzed cross-coupling reactions as previously described. Treatment ofcompounds of formula B2 with organoboron compounds A7 in the presence ofa catalyst such as PdCl₂(dppf), PdCl₂(dppe) Pd₂(dba)₃, Pd(dba)₂,PdCl₂(PPh₃)₂, Pd(PPh₃)₄ in a solvent such as PhCH₃, 1,4-dioxane, THF,DMA, DMF or DME in the presence of a base such as Na₂CO₃, K₂CO₃, Cs₂CO₃,CsF, KF, K₃PO₄, KOAc or the like and a ligand typically used in suchreactions such as Q-Phos, dppf, dppe or PPh₃ and the like affordscompounds of formula B3 at temperatures ranging from rt to 160° C. usingconventional or microwave heating.

The amine in compounds of formula B3 may be protected with a protectinggroup, as indicated by P¹, with previously described protecting groups.A preferred protecting group is t-butyl carbamate (Boc) ortrifluoroacetamide. The protecting group (P¹) on the nitrogen may beremoved as previously described or may be converted directly intocompounds of the formula B5. It will be generally recognized thatcompounds of the formula B4 represent a subset of compounds of formulaB5 where R¹ is equal to H. Compounds of formula B4 or B5 may beconverted to their corresponding salts using methods generally acceptedto those skilled in the art.

Compounds such as B5 may be prepared from compounds of the formula B4using methods such as reductive amination or alkylation. Thus treatmentof B4 with a compound containing a carbonyl, such as an aldehyde orketone, in the presence of a reductant such as NaBH₄, NaBH₃CN,NaBH(OAc)₃ or, hydrogen gas and presence of a catalyst, in a solventsuch as CH₂Cl₂, THF, DCE, MeOH, EtOH or similar affords compounds offormula B5. One skilled in the art will recognize that the addition ofacid to decrease the pH of the reaction mixture to less than pH 7 may berequired. One skilled in the art will also recognize that compounds offormula B5 may be obtained from B4 upon treatment with an alkylchloride, bromide, iodide, mesylate or tosylate and the like in asolvent such as DMF, DMA, THF or EtOH in the presence of bases such asNaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃.

Intermediates of formula C7 were prepared according to Scheme C.Compounds of the formula C1 may be prepared similar to compounds offormula A4 (Scheme 1). One skilled in the art will recognize thatcompounds of formula C1 can be utilized for transition-metal catalyzedcross-coupling reactions as previously described. Treatment of compoundsof formula C1 with organoboron compounds A7 in the presence of acatalyst such as PdCl₂(dppf), PdCl₂(dppe) Pd₂(dba)₃, Pd(dba)₂,PdCl₂(PPh₃)₂, Pd(PPh₃)₄ in a solvent such as PhCH₃, 1,4-dioxane, THF,DMA, DMF or DME in the presence of a base such as Na₂CO₃, K₂CO₃, Cs₂CO₃,CsF, KF, K₃PO₄, KOAc or the like and a ligand such as Q-Phos, dppf, dppeor PPh₃ and the like affords compounds of formula C2 at temperaturesranging from rt to 160° C. using conventional or microwave heating.Compounds of formula C3 were obtained from compounds of formula C2 uponhydrolysis of the compound obtained from the treatment of compounds offormula C2 with an oxidant such as m-chloroperoxybenzoic acid (m-CPBA)in CH₂Cl₂. One skilled in the art will recognize this transformation asa Baeyer-Villager oxidation. The hydrolysis is performed using a basesuch as NaOH or KOH in a solvent such as MeOH, EtOH or H₂O.

Compounds of the formula C5 were obtained from compounds of the formulaC3 upon treatment with a compound of the formula C4 or R⁶X where R⁶ maybe C₁₋₄alkyl, C₁₋₄cycloalkyl, isopropyl, cyclopropyl methyl,2-(trifluoromethyl)-ethyl and X maybe an alkyl chloride, bromide,iodide, mesylate or tosylate in a solvent such as DMF, DMA, THF or EtOHin the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃.

Compounds of the formula C5 may also be obtained from compounds of theformula C3 when in compound C4, X═OH using PPh₃ or similar trialkyl ortriaryl phosphine and diethyldiazodicarboxylate (DEAD),diisopropyldiazodicarboxylate (DIAD) or di-tert-butyldiazodicarboxylate(DBAD) in a solvent such as MeCN, DMF, THF or CH₂Cl₂ and the like. Oneskilled in the art will recognize this as a Mitsunobu reaction.

The amine in compounds of formula C5 may be protected with a protectinggroup, as indicated by P¹, with previously described protecting groups.A preferred protecting group is t-butyl carbamate (Boc) ortrifluoroacetamide. This protecting group (P¹) on the nitrogen may beremoved using previously described methods or may be converted directlyinto compounds of the formula C7. It will be generally recognized thatcompounds of the formula C5 represent a subset of compounds of formulaC7 where R¹ is equal to H. Compounds of formula C6 or C7 may beconverted to their corresponding salts using methods generally acceptedto those skilled in the art.

Compounds such as C7 were prepared from compounds of the formula C6using methods such as reductive amination or alkylation. Thus treatmentof C6 with a compound containing a carbonyl, such as an aldehyde orketone, in the presence of a reductant such as NaBH₄, NaBH₃CN,NaBH(OAc)₃ or hydrogen gas in the presence of a catalyst in a solventsuch as CH₂Cl₂, THF, DCE, MeOH, EtOH or similar affords compounds offormula C7. One skilled in the art will recognize that the addition ofacid to decrease the pH of the reaction mixture to less than pH 7 may berequired. One skilled in the art will also recognize that compounds offormula C7 may be obtained from C6 upon treatment with an alkylchloride, bromide, iodide, mesylate or tosylate and the like in asolvent such as DMF, DMA, THF or EtOH in the presence of bases such asNaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃.

Intermediates of formula D5 were prepared according to Scheme D.Compounds of the formula C2 were prepared similar to compounds offormula A4 (Scheme 1). Compounds of formula D1 were obtained fromcompounds of formula C2 by treatment with an oxidant such asm-chloroperoxybenzoic acid (m-CPBA) in CH₂Cl₂. One skilled in the artwill recognize that compounds of formula D1 may be converted tocompounds of formula D3 using amines D2 in the presence of a amidecoupling reagent such as EDC.HCl, HATU, PyBOP or the like and a basesuch as pyridine, triethylamine or diisopropylethylamine or the like ina suitable solvent such as DMF, CH₂Cl₂, THF or MeCN or the like.

The amine in compounds of formula D3 may be protected as indicated byP¹, with previously described protecting groups. A preferred protectinggroup is t-butyl carbamate (Boc) or trifluoroacetamide. This protectinggroup (P¹) on the nitrogen may be removed as previously described or maybe converted directly into compounds of the formula D5. It will begenerally recognized that compounds of the formula D4 represent a subsetof compounds of formula D5 where R¹ is equal to H. Compounds of formulaD4 or D5 may be converted to their corresponding salts using methodsgenerally accepted to those skilled in the art.

Compounds such as D5 were prepared from compounds of the formula D4using methods such as reductive amination or alkylation. Thus treatmentof D4 with a compound containing a carbonyl, such as an aldehyde orketone, in the presence of a reductant such as NaBH₄, NaBH₃CN,NaBH(OAc)₃ or hydrogen gas in the presence of a catalyst in a solventsuch as CH₂Cl₂, THF, DCE, MeOH, EtOH or similar affords compounds offormula D5. One skilled in the art will recognize that the addition ofacid to decrease the pH of the reaction mixture to less than pH 7 may berequired. One skilled in the art will also recognize that compounds offormula D5 may be obtained from D4 upon treatment with an alkylchloride, bromide, iodide, mesylate or tosylate and the like in asolvent such as DMF, DMA, THF or EtOH in the presence of bases such asNaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃ and the like.

Intermediates of formula E5 were prepared according to Scheme E.Compounds of formula E3 were synthesized from compounds of formula E1.Compounds of formula E2 may be obtained from compounds of formula E1using a compound of formula A3 in a suitable solvent such as DMF, DMSO,NMP or THF in the presence of a base such as NaH, KOtBu or Cs₂CO₃,preferably NaH in DMF. One skilled in the art will recognize thatcompounds of formula E2 can be utilized for transition-metal catalyzedcross-coupling reactions reactions as previously described. Treatment ofcompounds of formula E2 with organoboron compounds A7 in the presence ofa catalyst such as PdCl₂(dppf), PdCl₂(dppe) Pd₂(dba)₃, Pd(dba)₂,PdCl₂(PPh₃)₂, Pd(PPh₃)₄ in a solvent such as PhCH₃, 1,4-dioxane, THF,DMA, DMF or DME in the presence of a base such as Na₂CO₃, K₂CO₃, Cs₂CO₃,CsF, KF, K₃PO₄, KOAc or the like and a ligand such as Q-Phos, dppf, dppeor PPh₃ and the like affords compounds of formula E3 at temperaturesranging from rt to 160° C. using conventional or microwave heating.

Referring to Scheme 5, compounds of formula E4 were prepared fromcompounds of formula E3. The amine in compounds of formula E3 may beprotected with a protecting group, as indicated by P¹, with previouslydescribed protecting groups. A preferred protecting group is t-butylcarbamate (Boc) or trifluoroacetamide. This protecting group (P¹) on thenitrogen may be removed using previously described methods or may beconverted directly into compounds of the formula E5. It will begenerally recognized that compounds of the formula E4 represent a subsetof compounds of formula E5 where R¹ is equal to H. Compounds of formulaE4 or E5 may be converted to their corresponding salts using methodsgenerally accepted to those skilled in the art.

Compounds such as E5 were prepared from compounds of the formula E4using methods such as reductive amination or alkylation. Thus treatmentof E4 with a compound containing a carbonyl, such as an aldehyde orketone, in the presence of a reductant such as NaBH₄, NaBH₃CN,NaBH(OAc)₃ or hydrogen gas in the presence of a catalyst in a solventsuch as CH₂Cl₂, THF, DCE, MeOH, EtOH or similar affords compounds offormula E5. One skilled in the art will recognize that the addition ofacid to decrease the pH of the reaction mixture to less than pH 7 may berequired. One skilled in the art will also recognize that compounds offormula E5 may be obtained from E4 upon treatment with an alkylchloride, bromide, iodide, mesylate or tosylate and the like in asolvent such as DMF, DMA, THF or EtOH in the presence of bases such asNaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃ and the like.

Intermediates of formula F6 were prepared according to Scheme F.Compounds of formula F4 were synthesized from compounds of formula A3.Treatment of a compound of formula A3 with methanesulfonyl chloride inthe presence of a base such as pyridine, triethylamine ordiisopropylamine in a solvent such as CH₂Cl₂, THF or DCE yieldscompounds of formula F1. Treatment of a compound of formula F1 with anucleophile such as a compound of formula F2 in the presence of basesuch as pyridine, triethylamine, diisopropylamine, K₂CO₃, Cs₂CO₃ orNa₂CO₃ in a suitable solvent such as THF, CH₂Cl₂, DMF, MeCN, 1,4-dioxaneor the like at a temperature ranging from rt to 100° C. providescompounds of the formula F3.

One skilled in the art will recognize that compounds of formula F3 canbe utilized for transition-metal catalyzed cross-coupling reactions aspreviously described. Treatment of compounds of formula F3 withorganoboron compounds A7 in the presence of a catalyst such asPdCl₂(dppf), PdCl₂(dppe) Pd₂(dba)₃, Pd(dba)₂, PdCl₂(PPh₃)₂, Pd(PPh₃)₄ ina solvent such as PhCH₃, 1,4-dioxane, THF, DMA, DMF or DME in thepresence of a base such as Na₂CO₃, K₂CO₃, Cs₂CO₃, CsF, KF, K₃PO₄, KOAcor the like and a ligand such as Q-Phos, dppf, dppe or PPh₃ and the likeaffords compounds of formula F4 at temperatures ranging from rt to 160°C. using conventional or microwave heating.

The amine in compounds of formula F4 may be protected with a protectinggroup, as indicated by P¹, with previously described protecting groups.A preferred protecting group is t-butyl carbamate (Boc) ortrifluoroacetamide. This protecting group (P¹) on the nitrogen may beremoved as previously described or may be converted directly intocompounds of the formula F6. It will be generally recognized thatcompounds of the formula F5 represent a subset of compounds of formulaF6 where R¹ is equal to H. Compounds of formula F5 or F6 may beconverted to their corresponding salts using methods generally acceptedto those skilled in the art.

Compounds such as F6 were prepared from compounds of the formula F5using methods such as reductive amination or alkylation using methodsdescribed previously. One skilled in the art will recognize that theaddition of acid to decrease the pH of the reaction mixture to less thanpH 7 may be required. One skilled in the art will also recognize thatcompounds of formula F6 may be obtained from F5 upon treatment with analkyl chloride, bromide, iodide, mesylate or tosylate and the like in asolvent such as DMF, DMA, THF or EtOH in the presence of bases such asNaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃ and the like.

Intermediates of formula G6 were prepared according to Scheme G.Compounds of formula G4 were prepared from compounds of formula G1.Treatment of a compound of formula G1 with trifluoroacetic anhydride inthe presence of a base such as pyridine, triethylamine ordiisopropylethylamine or the like in a solvent such as CH₂Cl₂, THF, DMF,MeOH, EtOH or the like yields compounds of formula G2. Treatment ofcompounds of the formula G2 with an electrophilic bromine source such asBr₂, NBS, NaBr/oxone or the like in a solvent such as MeOH, CH₂Cl₂,EtOH, DMF, acetone, H₂O and the like or mixtures there of producescompounds of formula G3.

One skilled in the art will recognize that compounds of formula G3 canbe utilized for transition-metal catalyzed cross-coupling reactions aspreviously described. Treatment of compounds of formula G3 withorganoboron compounds A7 in the presence of a catalyst such asPdCl₂(dppf), PdCl₂(dppe) Pd₂(dba)₃, Pd(dba)₂, PdCl₂(PPh₃)₂, Pd(PPh₃)₄ ina solvent such as PhCH₃, 1,4-dioxane, THF, DMA, DMF or DME in thepresence of a base such as Na₂CO₃, K₂CO₃, Cs₂CO₃, CsF, KF, K₃PO₄, KOAcor the like and a ligand such as Q-Phos, dppf, dppe or PPh₃ and the likeaffords compounds of formula G4 at temperatures ranging from rt to 160°C. using conventional or microwave heating.

The amine in compounds of formula G4 may be protected withtrifluoroacetamide (as depicted). It will be generally recognized thatcompounds of the formula G5 represent a subset of compounds of formulaG6 where R¹ is equal to H. Compounds of formula G5 or G6 may beconverted to their corresponding salts using methods generally acceptedto those skilled in the art.

Compounds such as G6 were prepared from compounds of the formula G5using methods such as reductive amination or alkylation. Thus treatmentof G5 with a compound containing a carbonyl, such as an aldehyde orketone, in the presence of a reductant such as NaBH₄, NaBH₃CN,NaBH(OAc)₃ or hydrogen gas in the presence of a catalyst in a solventsuch as CH₂Cl₂, THF, DCE, MeOH, EtOH or similar affords compounds offormula G6. One skilled in the art will recognize that the addition ofacid to decrease the pH of the reaction mixture to less than pH 7 may berequired. One skilled in the art will also recognize that compounds offormula G6 may be obtained from G5 upon treatment with an alkylchloride, bromide, iodide, mesylate or tosylate and the like in asolvent such as DMF, DMA, THF or EtOH in the presence of bases such asNaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃ and the like.

Intermediates of formula H5 were prepared according to Scheme H.Compounds of formula H3 were prepared from compounds of the formula H1.One skilled in the art will recognize treatment of compounds of theformula H1 with a demethylating agent such as Lil in collidine, HBr inAcOH, or preferrably BBr₃ in CH₂Cl₂ would give compounds that can beconverted into precursors for transition-metal catalyzed cross-couplingreactions. For example, treatment of compounds of the formula H1 with atriflating agent such as trifluoromethanesulfonic anhydride (Tf₂O) orN-phenyltrifluoromethanesulfonamide in DCE, CH₂Cl₂, THF or the like inthe presence of a base such as pyridine, triethylamine ordiisopropylethylamine provides compounds of the formula H2. Treatment ofcompounds of formula H2 with organoboron compounds A7 in the presence ofa catalyst such as PdCl₂(dppf), PdCl₂(dppe) Pd₂(dba)₃, Pd(dba)₂,PdCl₂(PPh₃)₂, Pd(PPh₃)₄ in a solvent such as PhCH₃, 1,4-dioxane, THF,DMA, DMF or DME in the presence of a base such as Na₂CO₃, K₂CO₃, Cs₂CO₃,CsF, KF, K₃PO₄, KOAc or the like and a ligand such as Q-Phos, dppf, dppeor PPh₃ and the like affords compounds of formula H3 at temperaturesranging from rt to 160° C. using conventional or microwave heating.

The amine in compounds of formula H3 may be protected withtrifluoroacetamide (as depicted). It will be generally recognized thatcompounds of the formula H4 represent a subset of compounds of formulaH5 where R₂ is equal to H. Compounds of formula H4 or H5 may beconverted to their corresponding salts using methods generally acceptedto those skilled in the art.

Compounds such as H5 were prepared from compounds of the formula H4using methods such as reductive amination or alkylation, as previouslydescribed. One skilled in the art will recognize that the addition ofacid to decrease the pH of the reaction mixture to less than pH 7 may berequired. One skilled in the art will also recognize that compounds offormula H5 may be obtained from H4 upon treatment with an alkylchloride, bromide, iodide, mesylate or tosylate and the like in asolvent such as DMF, DMA, THF or EtOH in the presence of bases such asNaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃ and the like.

EXAMPLES Chemistry

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of practicing the invention. Those skilled in theart may find other methods of practicing the invention, which areobvious to them. However, those methods are deemed to be within thescope of this invention.

Thin-layer chromatography (TLC) was performed using Merck silica gel 60F₂₅₄ 2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography (PTLC) was performed usingEM Science silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates witha 20 cm×4 cm concentrating zone.

Normal-phase flash column chromatography (FCC) was performed on silicagel (SiO₂) eluting with 2 M NH₃ in MeOH/CH₂Cl₂ or EtOAc in hexanes,unless otherwise noted.

Preparative reversed-phase HPLC(RP HPLC) was performed on a HewlettPackard HPLC Series 1100, with a Phenomenex Luna C18 (5 μm, 4.6×150 mm)column. Detection was done at λ=230, 254 and 280 nm. The gradient was 10to 99% acetonitrile/H₂O (0.05% trifluoroacetic acid) over 5.0 min with aflow rate of 1 mL/min. Alternatively, HPLC was performed on a DionexAPS2000 LC/MS with a Phenomenex Gemini C18 (5 μm, 30×100 mm) column, anda gradient of 5 to 100% acetonitrile/H₂O (20 mM NH₄OH) over 16.3 min,and a flow rate of 30 mL/min. Preparative RP HPLC was also performed onan Agilent 1100 preparative system with a Waters X-Bridge C18 (5 μm,30×100 mm) column, and a gradient of 5 to 99% acetonitrile/H₂O (20 mMNH₄OH) over 17 min, and a flow rate of 80 mL/min.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. The format of the ¹H NMR data below is: chemicalshift in ppm downfield of the tetramethylsilane reference or relative toresidual protic solvent (multiplicity, coupling constant J in Hz,integration).

Chemical names were generated using ChemDraw Version 6.0.2(CambridgeSoft, Cambridge, Mass.).

General Procedure 1 (Removal of Boc Groups):

Boc groups were removed using TFA/CH₂Cl₂ (1:1) or 4M HCl indioxane/EtOAc (1:1). The compounds were then neutralized and extracted.Alternatively, compounds were characterized as the hydrochloride ortrifluoroacetate salt where indicated.

General Procedure 2 (Removal of Trifluoroacetamide Groups):

Trifluoroacetamide groups were removed using K₂CO₃ (1 eq.) in MeOH (0.2M) or 5M NH₄OH in MeOH. After 15 h, H₂O was added and the mixtureextracted with EtOAc. The combined organics were dried. Silica gelchromatography (1-7% 2M NH₃/MeOH in CH₂Cl₂) then provided thedeprotected amines.

General Procedure 3 (NH to NMe):

To amine in MeOH (0.1 M) was added excess 37 wt % [H₂CO]_(n) in H₂O andNaBHOAc₃ (1.2 eq.). After 18 h, 5% Na₂CO₃ (aq.) was added and themixture extracted with CH₂Cl₂. The combined organics were dried andpurified to yield the corresponding methylated analogs.

Example 1 3-(4-Methoxy-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine

Step A: Preparation of (4-Bromo-2-fluoro-benzylidene)-tert-butyl-amine

To a CH₂Cl₂ (900 mL) solution of 4-bromo-2-fluoro-benzaldehyde (50.0 g,246 mmol) was added tert-butylamine (42.3 mL, 29.3 g, 400 mmol) andMgSO₄ (60.0 g, 499 mmol). After 48 h the solution was filtered andconcentrated to give 62.0 g (98% yield) of4-Bromo-2-fluoro-benzylidene)-tert-butyl-amine as a yellow liquid. ¹HNMR (400 MHz, CDCl₃): 8.48 (s, 1H), 7.89 (t, J=8.1 Hz, 1H), 7.32-7.25(m, 2H), 1.29 (s, 9H).

Step B: Preparation of3-(5-Bromo-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butylester

To a 0° C. DMF (720 mL) solution of the title compound of Step A (37.2g, 144 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester(25.0 g, 144 mmol) was added NaH (60 wt % in mineral oil, 7.50 g, 188mmol) portionwise over 2 h. The reaction was then allowed to warm to rt.After 18 h, H₂O was added and the reaction mixture extracted with EtOAc(2×). The combined organic layers were washed with brine andconcentrated to give a yellow liquid that was treated with THF (360 mL),H₂O (360 mL) and AcOH (25 mL). After 5 h, this solution was made basicwith 5% Na₂CO₃ (aq.) and extracted with EtOAc (2×). The combined organiclayers were washed with brine and dried. The resulting solid was thentriturated with 20% EtOAc in hexanes to give 41.9 g (81.5%) of the titlecompound as a white solid. ¹H NMR (400 MHz, CDCl₃): 10.43 (s, 1H), 7.74(d, J=8.3 Hz, 1H), 7.26-7.23 (m, 1H), 6.77 (d, J=1.6 Hz, 1H), 5.01-4.95(m, 1H), 4.39 (ddd, J=9.9, 6.3, 0.8 Hz, 2H), 4.08 (dd, J=6.4, 0.8 Hz,2H), 1.46 (s, 9H).

Step C: Preparation of3-(5-Bromo-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester

To a CH₂Cl₂ (280 mL) solution of the title compound of Step B (24.7 g,69.4 mmol) was added m-CPBA (77 wt %, 23.3 g, 104 mmol). After 15 h, 10%Na₂S₂O₅ was added and the solution allowed to stir until the aqueous wasKl paper negative and extracted with CH₂Cl₂ (2×). The combined organiclayers were washed with saturated NaHCO₃ (aq.), concentrated and treatedwith MeOH (220 mL) and 1N NaOH (220 mL). After 15 h, the reaction waspartially concentrated to remove the MeOH and acidified with 1M KHSO₄(220 mL) then extracted with CH₂Cl₂ (2×). The combined organic layerswere washed with brine and dried to give a brown solid that wastriturated with EtOAc/hexanes giving 17.6 g (74% yield) of the titlecompound as a white solid. ¹H NMR (500 MHz, CDCl₃): 7.03 (dd, J=8.5, 2.1Hz), 1H), 6.84 (d, J=8.5 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 4.93-4.89 (m,1H), 4.34 (dd, J=10.1, 6.8 Hz, 1H), 4.03 (dd, J=9.9, 3.7 Hz, 1H), 1.46(s, 9H).

Step D: Preparation of3-(5-Bromo-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester

To the title compound of Step C (2.60 g, 7.54 mmol) and Cs₂CO₃ (2.70 g,8.30 mmol) in DMF (75 mL) was added iodomethane (2.14 g, 0.94 mL, 15.09mmol). After determined complete by TLC, saturated NaHCO₃ (aq.) wasadded and the mixture was extracted with CH₂Cl₂ (2×). The combinedorganic layers were dried. Silica gel chromatography (10-50% EtOAc inhexanes) gave 2.66 g (98%) of the title compound. MS (ESI): mass calcd.for C₁₅H₂₀BrNO₄, 357.06. m/z found, 304.1 [M-56]⁺, 382.1 [M+Na]⁺. ¹H NMR(CDCl₃): 7.08 (dd, J=8.6, 2.3 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.67 (d,J=2.2 Hz, 1H), 4.86 (tt, J=6.5, 4.3 Hz, 1H), 4.29 (ddd, J=9.7, 6.5, 0.8Hz, 2H), 4.08 (dd, J=10.1, 4.2 Hz, 2H), 3.85 (s, 3H), 1.44 (s, 9H).

Step E: Preparation of3-(4-Methoxy-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine-1-carboxylicacid tert-butyl ester

To title compound of Step D (0.106 g, 0.296 mmol),2-trifluoromethylphenylboronic acid (0.084 g, 0.444 mmol), K₃PO₄ (0.189g, 0.888 mmol), Pd(dba)₂ (0.007 g, 0.012 mmol) and QPhos (0.004 g, 0.006mmol) was added PhCH₃ (3 mL) and the reaction was heated to 80° C. for18 h. The reaction was cooled to rt, diluted with EtOAc, filteredthrough a small silica plug and concentrated. Silica gel chromatography(0-30% EtOAc in hexanes) gave 0.062 g (49%) of the title compound. MS(ESI): mass calcd. for C₂₂H₂₄F₃NO₄, 423.17. m/z found, 368.1 [M-56]⁺,446.2 [M+Na]⁺. ¹H NMR (CDCl₃): 7.73 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.3Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.93 (s, 2H),6.56 (s, 1H), 4.92-4.83 (m, 1H), 4.26 (dd, J=10.5, 6.5 Hz, 2H), 4.10(dd, J=10.5, 4.3 Hz, 2H), 3.93 (s, 3H), 1.43 (s, 9H).

Step F: Preparation of3-(4-Methoxy-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine

To title compound of Step E (0.062 g, 0.146 mmol) in EtOAc (2 mL) wasadded 4M HCl in dioxane (2 mL). After 18 h, the reaction was neutralizedwith saturated NaHCO₃ (aq.) and extracted with CH₂Cl₂ (2×). The combinedorganics were dried and concentrated. Silica gel chromatography (10-80%2M NH₃/MeOH in CH₂Cl₂) gave 0.029 g (61%) of the title compound. MS(ESI): mass calcd. for C₁₇H₁₆F₃NO₂, 323.11. m/z found, 324.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.73 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.3 Hz, 1H), 7.45 (t,J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.90 (td, J=8.2, 5.1 Hz, 2H),6.59 (s, 1H), 5.02-4.97 (m, 1H), 3.92 (s, 3H), 3.96-3.85 (m, 7H).

Unless otherwise specified the compounds in Examples 2-17 were preparedsimilar to Example 1 using the appropriately substituted arylboronicacid.

Example 2 3-(4′-Fluoro-4-methoxy-2′-methyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈FNO₂, 287.1. m/z found, 288.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.14 (dd, J=8.4, 6.0 Hz, 1H), 6.99-6.88 (m, 3H), 6.84 (dd,J=8.2, 2.0 Hz, 1H), 6.52 (d, J=2.0 Hz, 1H), 5.03-4.98 (m, 1H), 3.95-3.86(m, 7H), 2.24 (s, 3H).

Example 3 3′-(Azetidin-3-yloxy)-4′-methoxy-biphenyl-2-carbonitriletrifluoroacetate

MS (ESI): mass calcd. for C₁₇H₁₆N₂O₂, 280.1. m/z found, 281.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.73 (dd, J=7.7, 0.8 Hz, 1H), 7.63 (dt, J=7.8, 1.1 Hz, 1H),7.47 (d, J=7.8 Hz, 1H), 7.23 (dd, J=8.4, 2.0 Hz, 1H), 7.42 (dt, J=7.7,0.8 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.95 (d, J=1.9 Hz, 1H), 5.16 (s,1H), 4.46 (s, 2H), 4.35 (s, 2H), 3.91 (s, 3H).

Example 4 3-(4-Methoxy-2′,3′-dimethyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₈H₂₁NO₂, 283.2. m/z found, 284.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.17-7.10 (m, 2H), 7.06 (dd, J=7.0, 2.1 Hz, 1H), 6.93 (d,J=8.2 Hz, 1H), 6.87 (dd, J=8.2, 2.0 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H),5.02-4.96 (m, 1H), 3.92-3.88 (m, 7H), 2.34 (s, 3H), 2.16 (s, 3H).

Example 5 3-(3′-Fluoro-4-methoxy-2′-methyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈FNO₂, 287.1. m/z found, 288.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.20-7.15 (m, 1H), 7.00 (t, J=8.1 Hz, 2H), 6.94 (d, J=8.2Hz, 1H), 6.87 (dd, J=8.2, 2.0 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 5.03-4.99(m, 1H), 3.92-3.91 (m, 7H), 2.17 (d, J=2.5 Hz, 3H).

Example 6 3-(4-Methoxy-2′,6′-dimethyl-biphenyl-3-yloxy)-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₈H₂₁NO₂, 283.2. m/z found, 284.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.15 (dd, J=8.3, 6.6 Hz, 1H), 7.09 (d, J=7.6 Hz, 2H), 6.97(d, J=8.3 Hz, 1H), 6.81 (dd, J=8.2, 1.9 Hz, 1H), 6.51 (d, J=1.9 Hz, 1H),5.08-5.03 (m, 1H), 4.35-4.30 (m, 4H), 3.88 (s, 3H), 2.01 (s, 6H).

Example 7 3-(4-Methoxy-2′-trifluoromethoxy-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₇H₁₆F₃NO₃, 339.1. m/z found, 340.2 [M+H]⁺.¹H NMR (CDCl₃): 7.42-7.29 (m, 4H), 7.14 (dd, J=8.4, 2.1 Hz, 1H), 6.97(d, J=8.4 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 5.14-5.09 (m, 1H), 4.39-4.29(m, 4H), 3.89 (s, 3H).

Example 8 3-(4-Methoxy-2′-methyl-biphenyl-3-yloxy)-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₇H₁₉NO₂, 269.1. m/z found, 270.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.26-7.19 (m, 3H), 7.16 (d, J=6.6 Hz, 1H), 6.99 (dd, J=8.3,2.0 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.69 (d, J=2.0 Hz, 1H), 5.11-5.05(m, 1H), 4.49-4.34 (m, 4H), 3.88 (s, 3H), 2.24 (s, 3H).

Example 9 3-(4,2′-Dimethoxy-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₇H₁₉NO₃, 285.1. m/z found, 286.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.34-7.27 (m, 2H), 7.10 (dd, J=8.3, 2.1 Hz, 1H), 7.01 (dt,J=7.5, 1.0 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.88(d, J=2.0 Hz, 1H), 5.06-5.00 (m, 1H), 3.93-3.90 (m, 7H), 3.81 (s, 3H).

Example 103-(2′-Chloro-4-methoxy-6′-trifluoromethyl-biphenyl-3-yloxy)-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₇H₁₅ClF₃NO₂, 357.1. m/z found, 358.1 [M+H]⁺.¹H NMR (CDCl₃): 7.72 (s, 1H), 7.55 (dd, J=8.0, 1.2 Hz, 1H), 7.41 (d,J=8.0 Hz, 1H), 7.11 (dd, J=8.4, 2.0 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H),6.85 (d, J=2.0 Hz, 1H), 5.10 (s, 1H), 4.39-4.33 (m, 4H), 3.90 (s, 3H).

Example 11 3-(4-Methoxy-4′-methyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₇H₁₉NO₂, 269.1. m/z found, 270.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.38 (d, J=8.1 Hz, 2H), 7.23 (dd, J=11.6, 5.0 Hz, 3H), 6.95(dd, J=5.2, 3.2 Hz, 2H), 5.14-5.09 (m, 1H), 4.39-4.30 (m, 4H), 3.87 (s,3H), 2.38 (s, 3H).

Example 12 3-(4′-Fluoro-4-methoxy-3′-methyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈FNO₂, 287.1. m/z found, 288.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.33-7.22 (m, 2H), 7.09 (dd, J=8.3, 2.1 Hz, 1H), 7.07-7.01(m, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.77 (d, J=2.1 Hz, 1H), 5.11-5.06 (m,1H), 3.94-3.90 (m, 7H), 2.33 (d, J=1.8 Hz, 3H).

Example 13 3-(4-Methoxy-3′-methyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₇H₁₉NO₂, 269.1. m/z found, 270.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.35-7.21 (m, 4H), 7.14 (d, J=6.6 Hz, 1H), 6.97 (s, 1H),6.96 (d, J=6.6 Hz, 1H), 5.20-5.06 (m, 1H), 4.40-4.35 (m, 4H), 3.87 (s,3H), 2.41 (s, 3H).

Example 14 3-(4-Methoxy-3′,4′-dimethyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₈H₂₁NO₂, 283.2. m/z found, 284.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.28 (s, 1H), 7.24 (dd, J=8.0, 1.7 Hz, 1H), 7.18 (d, J=7.7Hz, 1H), 7.14 (dd, J=8.3, 2.1 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.82 (d,J=2.1 Hz, 1H), 5.13-5.04 (m, 1H), 3.99-3.87 (m, 7H), 2.32 (s, 3H), 2.29(s, 3H).

Example 15 3-(4-Methoxy-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₆H₁₇NO₂, 255.1. m/z found, 256.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.53-7.47 (m, 2H), 7.44-7.37 (m, 2H), 7.34-7.27 (m, 1H),7.16 (dd, J=8.3, 2.1 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.85 (d, J=2.1 Hz,1H), 5.11-5.05 (m, 1H), 3.96-3.90 (m, 7H).

Example 16 3-(4-Methoxy-2′,5′-dimethyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₈H₂₁NO₂, 283.2. m/z found, 284.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.14 (d, J=7.7 Hz, 1H), 7.06 (d, J=7.7 Hz, 1H), 7.03 (s,1H), 6.93 (d, J=8.2 Hz, 1H), 6.88 (dd, J=8.2, 2.0 Hz, 1H), 6.57 (d,J=2.0 Hz, 1H), 5.03-4.98 (m, 1H), 3.91-3.90 (m, 7H), 2.34 (s, 3H), 2.22(s, 3H).

Example 17 3-(2′-Chloro-4-methoxy-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₆H₁₆ClNO₂, 289.1. m/z found, 290.2 [M+H]⁺.¹H NMR (CDCl₃): 7.46 (dd, J=7.6, 1.4 Hz, 1H), 7.35-7.22 (m, 3H), 7.01(dd, J=8.3, 2.0 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H),5.06-5.01 (m, 1H), 3.95-3.90 (m, 7H).

Example 183-(2′-Chloro-4-methoxy-biphenyl-3-yloxy)-1-isopropyl-azetidinetrifluoroacetate

To the title compound of Example 17 (0.13 g, 0.44 mmol) in DCE was addedacetone (0.5 mL) and NaBH(OAc)₃ (0.14 g, 0.66 mmol). After 18 h,saturated NaHCO₃ (aq.) was added and the mixture extracted with CH₂Cl₂(2×). The combined organics were dried. Silica gel chromatography(10-80% 2M NH₃/MeOH in CH₂Cl₂) gave the title compound. MS (ESI): masscalcd. for C₁₉H₂₂ClNO₂, 331.13. m/z found, 332.2 [M+H]⁺. ¹H NMR (CDCl₃):7.45 (dd, J=8.1, 1.5 Hz, 1H), 7.33-7.24 (m, 3H), 7.12 (dd, J=8.4, 2.1Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 5.09-4.97 (m,1H), 4.77-4.73 (m, 2H), 3.95-3.81 (m, 6H), 2.35-2.23 (m, 4H), 2.05-1.91(m, 1H), 1.89-1.81 (m, 1H).

Example 193-(2′-Chloro-4-methoxy-biphenyl-3-yloxy)-1-cyclobutyl-azetidinetrifluoroacetate

Prepared according to Example 18 using cyclobutanone. MS (ESI): masscalcd. for C₂₀H₂₂ClNO₂, 343.13. m/z found, 345.2 [M+H]⁺. ¹H NMR (CDCl₃):7.45 (d, J=7.7 Hz, 1H), 7.34-7.24 (m, 3H), 7.12 (dd, J=8.4, 2.0 Hz, 1H),6.98 (d, J=8.4 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 5.09-5.04 (m, 1H),4.84-4.68 (m, 2H), 3.95-3.86 (m, 5H), 3.34 (s, 1H), 1.34-1.33 (m, 6H).

Example 20 3-(2′-Trifluoromethyl-biphenyl-3-yloxy)-azetidine

Step A: Preparation of 3-Methanesulfonyloxy-azetidine-1-carboxylic acidtert-butyl ester

To 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.21 g, 6.99mmol) and Et₃N (0.85 g, 1.2 mL, 8.4 mmol) in CH₂Cl₂ (35 mL) at 0° C. wasadded methanesulfonyl chloride (0.88 g, 0.60 mL, 7.7 mmol). After 1 h,brine was added and the reaction extracted with CH₂Cl₂ (2×). Thecombined organics were dried to give 1.65 g (94%) of3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester ayellow solid that was used without further purification. ¹H NMR (CDCl₃):5.20 (tt, J=6.7, 4.2 Hz, 1H), 4.28 (ddd, J=10.3, 6.7, 1.2 Hz, 2H), 4.10(ddd, J=10.4, 4.2, 1.1 Hz, 2H), 3.07 (s, 3H), 1.44 (s, 9H).

Step B: Preparation of 3-(3-Bromo-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester

To 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester(0.795 g, 3.16 mmol) and Cs₂CO₃ (1.13 g, 3.48 mmol) in DMF (30 mL) wasadded 3-bromophenol (0.547 g, 3.16 mmol). The reaction was heated to 80°C. for 18 h, then cooled to rt. Brine was added and the mixtureextracted with Et₂O (2×). The combined organics were washed with brineand dried. Silica gel chromatography (0-40% EtOAc in hexanes) gave 0.881g (85%) of the title compound. MS (ESI): mass calcd. for C₁₄H₁₈BrNO₃,327.05; m/z found, 272.0 [M-56]⁺. ¹H NMR (CDCl₃): 7.17-7.11 (m, 2H),6.90-6.88 (m, 1H), 6.70-6.66 (m, 1H), 4.89-4.82 (m, 1H), 4.30 (ddd,J=9.7, 6.4, 0.9 Hz, 2H), 3.99 (dd, J=10.3, 4.1 Hz, 2H), 1.45 (s, 9H).

Step C: Preparation of3-(2′-Trifluoromethyl-biphenyl-3-yloxy)-azetidine-1-carboxylic acidtert-butyl ester

Prepared from the title compound of Step B as described in Example 1Step E. MS (ESI): mass calcd. for C₂₁H₂₂F₃NO₃, 393.16. m/z found, 338.1[M-56]⁺. ¹H NMR (CDCl₃): 7.74 (d, J=7.8 Hz, 1H), 7.55 (dd, J=7.5, 7.0Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.34-7.26 (m, 1H), 6.95 (d, J=7.6 Hz,1H), 6.78 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 6.70 (s, 1H), 4.91-4.84 (m,1H), 4.28 (ddd, J=9.7, 6.4, 0.8 Hz, 2H), 4.02 (dd, J=10.3, 4.1 Hz, 2H),1.45 (s, 9H).

Step D: Preparation of 3-(2′-Trifluoromethyl-biphenyl-3-yloxy)-azetidine

Prepared from the title compound of Step C as described in Example 1Step F. MS (ESI): mass calcd. for C₁₆H₁₄F₃NO, 293.10. m/z found, 294.2[M+H]⁺. ¹H NMR (CDCl₃): 7.74 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.3 Hz, 1H),7.46 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.29 (t, J=7.9 Hz, 1H),6.92 (d, J=7.6 Hz, 1H), 6.79 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 6.71 (s,1H), 5.04-4.99 (m, 1H), 3.92 (dd, J=9.4, 6.5 Hz, 2H), 3.82 (dd, J=9.5,5.9 Hz, 2H).

Unless otherwise specified the compounds in Examples 21-23 were preparedsimilar to Example 20 using the appropriately substituted arylboronicacid.

Example 21 3-(2′-Chloro-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₅H₁₄ClNO, 259.08. m/z found, 260.1 [M+H]⁺.¹H NMR (CDCl₃): 7.52-7.42 (m, 1H), 7.34-7.26 (m, 4H), 7.03-7.01 (m, 1H),6.86-6.82 (m, 1H), 6.80-6.77 (m, 1H), 5.05 (s, 1H), 3.95 (s, 4H).

Example 22 3-(3′-Methyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₆H₁₇NO, 239.13. m/z found, 240.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.36 (d, J=9.2 Hz, 1H), 7.32 (t, J=7.8 Hz, 2H), 7.18 (t,J=6.9 Hz, 2H), 6.99-6.97 (m, 1H), 6.73 (dd, J=8.1, 2.4 Hz, 1H),5.08-5.03 (m, 1H), 3.98-3.91 (m, 2H), 3.98-3.91 (m, 2H), 2.41 (s, 3H).

Example 23 3-(2′-Methyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₆H₁₇NO, 239.13. m/z found, 240.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.30 (t, J=7.8 Hz, 1H), 7.27-7.18 (m, 4H), 6.93-6.90 (m,1H), 6.77-6.67 (m, 2H), 5.04-4.99 (m, 1H), 3.95-3.91 (m, 2H), 3.84-3.81(m, 2H), 2.27 (s, 3H).

Unless otherwise specified the compounds in Examples 24-27 were preparedsimilar to Example 20 Steps A-D using3-(5-Bromo-2-chloro-phenoxy)-azetidine-1-carboxylic acid tert-butylester (prepared according to Example 20 Step B using5-Bromo-2-chloro-phenol) and the appropriate boronic acid.

Example 24 3-(4,2′-Dichloro-biphenyl-3-yloxy)-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₅H₁₃Cl₂NO, 293.04. m/z found, 294.1 [M+H]⁺.¹H NMR (CDCl₃): 7.48-4.73 (m, 2H), 7.33-7.26 (m, 3H), 7.05 (dd, J=8.2,1.8 Hz, 1H), 6.71 (d, J=1.8 Hz, 1H), 5.25-5.11 (m, 1H), 4.46-4.42 (m,2H), 4.32-4.29 (m, 2H).

Example 25 3-(4-Chloro-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₆H₁₃ClF₃NO, 327.06. m/z found, 328.1 [M+H]⁺.¹H NMR (CDCl₃): 7.74 (d, J=7.7 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.49 (t,J=7.6 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H), 6.95 (dd,J=8.1, 1.7 Hz, 1H), 6.58 (d, J=0.9 Hz, 1H), 5.17-5.11 (m, 1H), 4.44-4.39(m, 2H), 4.30-4.26 (m, 2H).

Example 26 3-(4-Chloro-2′-methyl-biphenyl-3-yloxy)-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₆H₁₆ClNO, 273.09. m/z found, 274.1 [M+H]⁺.¹H NMR (CDCl₃): 7.40 (d, J=8.1 Hz, 1H), 7.30-7.19 (m, 3H), 7.13 (d,J=7.3 Hz, 1H), 6.95 (dd, J=8.1, 1.8 Hz, 1H), 6.56 (d, J=1.8 Hz, 1H),5.23-5.03 (m, 1H), 4.45-4.41 (m, 2H), 4.32-4.31 (m, 2H), 2.22 (s, 3H).

Example 27 3-(4-Chloro-3′-methyl-biphenyl-3-yloxy)-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₆H₁₆ClNO, 273.09. m/z found, 274.2 [M+H]⁺.¹H NMR (CDCl₃): 7.39 (d, J=8.2 Hz, 1H), 7.34-7.25 (m, 3H), 7.17 (dd,J=8.2, 1.9 Hz, 2H), 6.81 (d, J=1.9 Hz, 1H), 5.24-5.18 (m, 1H), 4.44-4.39(m, 2H), 4.30-4.26 (m, 2H), 2.40 (s, 3H).

Example 283-(Azetidin-3-yloxy)-2′-trifluoromethyl-biphenyl-4-carbonitrile

Step A: Preparation of3-(5-Bromo-2-cyano-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

To a solution of 4-bromo-2-fluoro-benzonitrile (1.0 g, 5.0 mmol) and3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (0.95 g, 5.5mmol) in DMF (15 mL) at 0° C., was added NaH (60% in mineral oil, 130mg, 5.5 mmol). After 18 h, H₂O and EtOAc were added and the organicportion washed with brine (3×) and dried to provide the title compound(1.4 g, 79%). MS (ESI): mass calcd. for C₁₅H₁₇BrN₂O₃, 352.0. m/z found,377.1 [M+Na]⁺. ¹H NMR (CDCl₃): 7.48 (d, J=8.2 Hz, 1H), 7.25 (dd, J=8.2,1.7 Hz, 1H), 6.79 (d, J=1.6 Hz, 1H), 5.00-4.92 (m, 1H), 4.38 (ddd,J=9.9, 6.4, 1.1 Hz, 2H), 4.11 (dd, J=10.0, 3.8 Hz, 2H), 1.48 (s, 9H).

Step B: Preparation of3-(4-Cyano-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine-1-carboxylicacid tert-butyl ester

Prepared from the title compound of Step A according to Example 1 Step Eusing 2-trifluoromethylphenylboronic acid.

Step C: Preparation of3-(Azetidin-3-yloxy)-2′-trifluoromethyl-biphenyl-4-carbonitrile

Prepared from the title compound of Step B according to generalprocedure 1. MS (ESI): mass calcd. for C₁₇H₁₃F₃N₂O, 318.1. m/z found,319.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.78 (d, J=7.7 Hz, 1H), 7.64-7.57 (m, 2H),7.55 (dd, J=7.7, 7.6 Hz, 1H), 6.99 (dd, J=7.9, 1.2 Hz, 1H), 6.64 (s,1H), 5.12-5.03 (m, 1H), 4.01-3.86 (m, 4H), 2.69-2.54 (m, 1H).

Example 29 3-(Azetidin-3-yloxy)-biphenyl-4-carbonitrile

Prepared according to Example 28 using phenylboronic acid. MS (ESI):mass calcd. for C₁₆H₁₄N₂O, 250.1. m/z found, 251.2 [M+H]⁺. ¹H NMR(CDCl₃): 7.65 (d, J=8.0 Hz, 1H), 7.56-7.52 (m, 2H), 7.52-7.47 (m, 2H),7.46-7.42 (m, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.85 (s, 1H), 5.21-5.13 (m,1H), 4.03-3.91 (m, 4H), 1.97-1.90 (br m, 1H).

Example 30 3-(Azetidin-3-yloxy)-2′-methyl-biphenyl-4-carbonitrile

Prepared according to Example 28 using 2-methylphenylboronic acid. MS(ESI): mass calcd. for C₁₇H₁₆N₂O, 264.1. m/z found, 265.3 [M+H]⁺. ¹H NMR(CDCl₃): 7.62 (d, J=7.9 Hz, 1H), 7.38-7.24 (m, 3H), 7.18 (d, J=7.4 Hz,1H), 7.00 (d, J=9.1 Hz, 1H), 6.62 (s, 1H), 5.20-5.01 (m, 1H), 4.04-3.83(m, 4H), 2.26 (s, 3H).

Example 31 5-(Azetidin-3-yloxy)-2-methyl-biphenyl-4-carbonitrile

Step A: Preparation of3-(5-Bromo-2-cyano-4-methyl-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester

Prepared according to Example 28 using4-bromo-2-fluoro-5-methyl-benzonitrile (1.0 g, 4.7 mmol),3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 6.5mmol), DMF (20 mL) and NaH (60% in mineral oil, 156 mg, 6.5 mmol) toprovide the title compound (1.3 g, 74%). MS (ESI): mass calcd. forC₁₆H₁₉BrN₂O₃, 366.1. m/z found, 389.1 [M+Na]⁺. ¹H NMR (CDCl₃): 7.45 (s,1H), 6.83 (s, 1H), 4.97-4.88 (m, 1H), 4.35 (ddd, J=9.8, 6.4, 0.9 Hz,1H), 4.09 (dd, J=10.0, 3.9 Hz, 1H), 2.36 (s, 3H), 1.47 (s, 9H).

Step B: Preparation of3-(4-Cyano-6-methyl-biphenyl-3-yloxy)-azetidine-1-carboxylic acidtert-butyl ester

Prepared from the title compound of Step A as described in Example 1Step E using phenylboronic acid.

Step C: Preparation of5-(Azetidin-3-yloxy)-2-methyl-biphenyl-4-carbonitrile

Prepared from the title compound of Step B according to generalprocedure 1. ¹H NMR (CDCl₃): 7.48-7.36 (m, 4H), 7.31-7.22 (m, 2H), 6.53(s, 1H), 5.11-4.99 (m, 1H), 4.02-3.83 (m, 4H), 2.19 (s, 3H).

Example 32 3-(4-Ethoxy-2′-methyl-biphenyl-3-yloxy)-azetidinehydrochloride

Step A: Preparation of3-(4-Formyl-2′-methyl-biphenyl-3-yloxy)-azetidine-1-carboxylic acidtert-butyl ester

To 3-(5-Bromo-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butylester (1.4 g, 3.9 mmol), 2-methylphenylboronic acid (0.55 g, 4.1 mmol),K₃PO₄ (2.5 g, 11.7 mmol), Pd(dba)₂ (0.046 g, 0.080 mmol) and QPhos(0.114 g, 0.160 mmol) was added PhCH₃ (16 mL). After 18 h at rt thereaction was diluted with EtOAc and filtered through a small silica pad.Silica gel chromatography (10-40% EtOAc in hexanes) gave 1.42 g (98%yield) of the title compound. ¹H NMR (CDCl₃): 7.26-7.18 (m, 4H), 6.94(d, J=8.3 Hz, 1H), 6.90 (dd, J=8.2, 2.0 Hz, 1H), 6.55 (d, J=1.9 Hz, 1H),4.90-4.86 (m, 1H), 4.26 (dd, J=10.1, 6.3 Hz, 2H), 4.12 (m, 4H), 2.26 (s,3H), 1.49 (t, J=7.0 Hz, 3H), 1.44 (s, 9H).

Step B: Preparation of3-(4-Hydroxy-2′-methyl-biphenyl-3-yloxy)-azetidine-1-carboxylic acidtert-butyl ester

To a CH₂Cl₂ (6 mL) solution of the title compound of Step A (1.40 g,3.81 mmol) was added m-CPBA (77 wt %, 1.30 g, 5.70 mmol). After 15 h, 10wt % Na₂S₂O₅ (aq.) was added and the solution allowed to stir until theaqueous was Kl paper negative and extracted with CH₂Cl₂ (2×). Thecombined organic layers were washed with saturated NaHCO₃ (aq.),concentrated and treated with MeOH (30 mL) and 1N NaOH (15 mL). After 15h, the reaction was partially concentrated to remove the MeOH andacidified with 1M KHSO₄ then extracted with EtOAc (2×). The combinedorganic layers were dried and concentrated to give the 1.1 g of thetitle compound that was used in the next step without furtherpurification.

Step C: Preparation of 3-(4-Ethoxy-2′-methyl-biphenyl-3-yloxy)-azetidinehydrochloride

Prepared according to Example 1 Steps D and F using iodoethane. MS(ESI): mass calcd. for C₁₈H₂₁NO₂, 283.16. m/z found, 284.3 [M+H]⁺. ¹HNMR (DMSO-D₆): 9.26 (s, 2H), 7.28-7.17 (m, 4H), 7.08 (d, J=8.3 Hz, 1H),6.93 (dd, J=8.3, 2.1 Hz, 1H), 6.74 (d, J=2.1 Hz, 1H), 5.06-5.01 (m, 1H),4.40 (dd, J=12.4, 6.7 Hz, 2H), 4.10 (q, J=7.0 Hz, 2H), 4.05-4.01 (m,2H), 2.23 (s, 3H), 1.37 (t, J=7.0 Hz, 3H).

Unless otherwise specified the compounds in Examples 33-36 were preparedsimilar to Example 32 using the appropriate alkyl halide.

Example 333-[2′-Methyl-4-(2,2,2-trifluoro-ethoxy)-biphenyl-3-yloxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₈F₃NO₂, 337.13. m/z found, 338.3 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.27-7.18 (m, 4H), 7.04 (d, J=8.2 Hz, 1H), 6.87(dd, J=8.2, 2.0 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 5.03-4.98 (m, 1H), 4.40(d, J=8.4 Hz, 2H), 3.93-3.85 (m, 4H), 2.25 (s, 3H).

Example 34 3-(4-Cyclobutoxy-2′-methyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₂₀H₂₃NO₂, 309.17. m/z found, 311.3 [M+H]⁺. ¹HNMR (500 MHz, DMSO-D₆): 9.26 (s, 2H), 7.28-7.17 (m, 4H), 6.93-6.89 (m,2H), 6.73 (d, J=1.6 Hz, 1H), 5.06-5.01 (m, 1H), 4.74-4.69 (m, 1H), 4.38(dd, J=11.7, 6.7 Hz, 2H), 4.02 (dd, J=11.7, 4.7 Hz, 2H), 2.49-2.43 (m,2H), 2.23 (s, 3H), 2.14-2.06 (m, 2H), 1.84-1.77 (m, 1H), 1.70-1.61 (m,1H).

Example 35 3-(4-Cyclopropylmethoxy-2′-methyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₂₀H₂₃NO₂, 309.17. m/z found, 311.3 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 7.25-7.19 (m, 4H), 6.93 (d, J=8.2 Hz, 1H), 6.85(dd, J=8.2, 2.1 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 5.03-4.98 (m, 1H),3.91-3.88 (m, 6H), 2.27 (s, 3H), 1.39-1.31 (m, 1H), 0.67-0.64 (m, 2H),0.39-0.36 (m, 2H).

Example 36 3-(4-Isopropoxy-2′-methyl-biphenyl-3-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₉H₂₃NO₂, 297.17. m/z found, 298.3 [M+H]⁺. ¹HNMR (500 MHz, DMSO-D₆): 9.18 (s, 2H), 7.28-7.18 (m, 4H), 7.09 (d, J=8.5Hz, 1H), 6.93 (dd, J=8.3, 2.1 Hz, 1H), 6.75 (d, J=2.1 Hz, 1H), 5.04-4.99(m, 1H), 4.65-4.60 (m, 1H), 4.38 (dd, J=12.4, 6.7 Hz, 2H), 4.02 (dd,J=12.4, 5.0 Hz, 1H), 2.24 (s, 3H), 1.31 (d, J=6.0 Hz, 6H).

Example 37 3-(Azetidin-3-yloxy)-2′-trifluoromethyl-biphenyl-4-carboxylicacid diethylamide

Step A: Preparation of3-(4-Formyl-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine-1-carboxylicacid tert-butyl ester

To the title compound of Example 1 Step B (0.20 g, 0.56 mmol),2-trifluoromethylphenylboronic acid (0.16 g, 0.84 mmol), K₃PO₄ (0.357 g,1.68 mmol) Pd(dba)₂ (0.013 g, 0.022 mmol) and Q-Phos (0.008 g, 0.011mmol) was added PhCH₃. After 48 h at rt the reaction was diluted withEtOAc and filtered through a small silica pad. Silica gel chromatography(0-30% EtOAc in hexanes) gave 0.24 g (99% yield) of the title compound.MS (ESI): mass calcd. for C₂₂H₂₂F₃NO₄, 421.15. m/z found, 336.1 [M-56]⁺,444.1 [M+Na]⁺. ¹H NMR (CDCl₃): 10.53 (d, J=0.7 Hz, 1H), 7.91 (d, J=7.9Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.3 Hz, 1H), 7.54 (t, J=7.6Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.05 (d, J=7.9 Hz, 1H), 6.59 (s, 1H),4.99 (tt, J=6.4, 4.0 Hz, 1H), 4.37-4.29 (m, 2H), 4.11-4.08 (m, 2H), 1.45(s, 9H).

Step B: Preparation of3-(4-Carboxy-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine-1-carboxylicacid tert-butyl ester

To a CH₂Cl₂ (6 mL) solution of the title compound of Step A (0.236 g,0.560 mmol) was added m-CPBA (77 wt %, 0.189 g, 0.840 mmol). After 15 h,10% Na₂S₂O₅ was added and the solution allowed to stir until the aqueouswas Kl paper negative and extracted with CH₂Cl₂ (2×). The combinedorganic layers were dried and treated with MeOH (10 mL) and 1N NaOH (10mL). After 15 h, the reaction was partially concentrated to remove theMeOH and acidified with 1M HCl (220 mL) then extracted with EtOAc (2×).The combined organic layers were dried and concentrated. Silica gelchromatography (0-30% EtOAc in hexanes) gave 0.091 g (37% yield) of thetitle compound. (MS (ESI): mass calcd. for C₂₂H₂₂F₃NO₅, 437.15. m/zfound, 382.1 [M-56]⁺, 460.1 [M+Na]⁺. ¹H NMR (CDCl₃): 7.73 (d, J=7.8 Hz,1H), 7.55 (t, J=7.5 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.6 Hz,1H), 6.99 (d, J=8.2 Hz, 1H), 6.87 (dd, J=8.2, 1.9 Hz, 1H), 6.52 (d,J=1.0 Hz, 1H), 4.97-4.88 (m, 1H), 4.30 (dd, J=9.8, 6.4 Hz, 2H), 4.05(dd, J=9.9, 3.7 Hz, 2H), 1.45 (s, 9H)) and 0.091 g (39% yield) of3-(4-Hydroxy-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine-1-carboxylicacid tert-butyl ester (MS (ESI): mass calcd. for C₂₁H₂₂F₃NO₄, 409.15.m/z found, 354.1 [M-56]⁺, 432.1 [M+Na]⁺. ¹H NMR (CDCl₃): 8.19 (d, J=8.0Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.54 (t, J=7.5Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.12 (dd, J=8.0, 1.3 Hz, 1H), 6.63 (s,1H), 5.11-5.00 (m, 1H), 4.36 (dd, J=10.1, 6.4 Hz, 2H), 4.12 (dd, J=10.6,3.6 Hz, 2H), 1.45 (s, 9H).

Step C: Preparation of3-(4-Diethylcarbamoyl-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine-1-carboxylicacid tert-butyl ester

To the title compound of Step B (0.09 g, 0.21 mmol) in CH₂Cl₂ (2 mL) wasadded HOBt (0.003 g, 0.02 mmol), Et₃N (0.03 mL, 0.02 g, 0.23 mmol),Et₂NH (0.02 g, 0.02 mL, 0.23 mmol) and EDC.HCl (0.04 g, 0.23 mmol).After 18 h, saturated NaHCO₃ (aq.) was added and the reaction extractedwith CH₂Cl₂ (2×). The combined organics were dried. Silica gelchromatography (0-60% EtOAc in hexanes) gave 0.082 g (80% yield) of thetitle compound. MS (ESI): mass calcd. for C₂₆H₃₁F₃N₂O₄, 492.22. m/zfound, 437.2 [M-56]⁺, 493.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.75 (d, J=7.7 Hz,1H), 7.58 (t, J=7.4 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.5 Hz,1H), 7.28 (d, J=7.6 Hz, 1H), 6.99 (dd, J=7.6, 1.2 Hz, 1H), 6.51 (s, 1H),4.93-4.83 (m, 1H), 4.25 (dd, J=9.6, 6.5 Hz, 2H), 4.01 (s, 1H), 3.94 (s,1H), 3.79 (s, 1H), 3.41 (s, 1H), 3.21 (q, J=7.1 Hz, 2H), 1.44 (s, 9H),1.28 (t, J=7.1 Hz, 3H), 1.10 (t, J=7.1 Hz, 3H).

Step D: Preparation of3-(Azetidin-3-yloxy)-2′-trifluoromethyl-biphenyl-4-carboxylic aciddiethylamide

Prepared from the title compound of Step C according to generalprocedure 1. MS (ESI): mass calcd. for C₂₁H₂₃F₃N₂O₂, 392.17. m/z found,393.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.74 (d, J=7.3 Hz, 1H), 7.57 (t, J=7.2 Hz,1H), 7.48 (t, J=7.5 Hz, 1H), 7.33 (t, J=8.9 Hz, 1H), 7.25 (d, J=7.7 Hz,1H), 6.95 (dd, J=7.7, 1.3 Hz, 1H), 6.56 (s, 1H), 5.03-4.97 (m, 1H),3.90-3.78 (m, 2H), 3.22 (q, J=7.1 Hz, 2H), 1.96 (s, 2H), 1.27 (t, J=7.1Hz, 3H), 1.10 (t, J=7.1 Hz, 3H).

Example 38 3-(4-Chloro-3′-methyl-biphenyl-2-yloxy)-azetidine

Step A: Preparation of3-(5-Chloro-2-trifluoromethanesulfonyloxy-phenoxy)-azetidine-1-carboxylicacid tert-butyl ester

To 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester (2.0 g, 6.7 mmol) in CH₂Cl₂ (34 mL) at 0° C. was added Et₃N (0.74g, 1.0 mL, 7.3 mmol) and Tf₂O (2.0 g, 7.0 mmol). After warming to rt,H₂O was added and the mixture extracted with CH₂Cl₂ (2×). The combinedorganics were dried. Silica gel chromatography (5-25%) gave 1.12 g (39%)of the title compound as a white solid. ¹H NMR (CDCl₃): 7.20 (d, J=8.7Hz, 1H), 7.03 (dd, J=8.7, 2.3 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 4.95-4.91(m, 1H), 4.34 (ddd, J=10.0, 6.4, 1.0 Hz, 2H), 4.08-4.04 (m, 2H), 1.46(s, 9H).

Step B: Preparation of3-(4-Chloro-3′-methyl-biphenyl-2-yloxy)-azetidine-1-carboxylic acidtert-butyl ester

To the title compound of Step A (0.12 g, 0.27 mmol),3-methylphenylboronic acid (0.08 g, 0.60 mmol), K₃PO₄ (0.128 g, 0.54mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.013 g, 0.017 mmol) and dppf (0.006 g, 0.010mmol) was added dioxane (3 mL). The flask was heated at 100° C. for 18h, cooled to rt, diluted with EtOAc and filtered through a small silicapad. Silica gel chromatography (10-40% EtOAc in hexanes) gave 0.073 g(72% yield) of the title compound. ¹H NMR (CDCl₃): 7.31-7.26 (m, 4H),7.18-7.15 (m, 1H), 7.05 (dd, J=8.2, 2.0 Hz, 1H), 6.57 (d, J=1.9 Hz, 1H),4.86-4.81 (m, 1H), 4.30-4.26 (m, 2H), 3.96 (dd, J=10.2, 4.2 Hz, 2H),2.40 (s, 3H), 1.44 (s, 9H).

Step C: Preparation of 3-(4-Chloro-3′-methyl-biphenyl-2-yloxy)-azetidine

Prepared according to Example 1 Step F. MS (ESI): mass calcd. forC₁₆H₁₆ClNO, 273.09. m/z found, 274.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.34-7.24(m, 4H), 7.16-7.14 (m, 1H), 7.01 (dd, J=8.2, 2.0 Hz, 1H), 6.62 (d, J=2.0Hz, 1H), 4.99-4.92 (m, 1H), 3.92-3.88 (m, 2H), 3.76-3.74 (m, 2H), 2.40(s, 3H).

Unless otherwise specified the compounds in Examples 39-42 were preparedsimilar to Example 38 using the appropriate arylboronic acid.

Example 39 3-(4-Chloro-2′-methyl-biphenyl-2-yloxy)-azetidine

Prepared according to Example 38 using 2-methylphenylboronic acid. MS(ESI): mass calcd. for C₁₆H₁₆ClNO, 273.1. m/z found, 274.0 [M+H]⁺. ¹HNMR (CDCl₃): 7.29-7.20 (m, 3H), 7.14-7.07 (m, 2H), 7.01 (dd, J=8.1, 1.9Hz, 1H), 6.62 (d, J=1.9 Hz, 1H), 4.95-4.89 (m, 1H), 3.84-3.66 (m, 4H),2.16 (s, 3H).

Example 40 3-(4-Chloro-3′-trifluoromethyl-biphenyl-2-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₆H₁₃ClF₃NO, 327.06. m/z found, 328.0 [M+H]⁺.¹H NMR (CDCl₃): 7.80 (s, 1H), 7.70-7.68 (m, 1H), 7.60-7.58 (m, 1H),7.54-7.50 (m, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.05 (dd, J=8.2, 2.0 Hz, 1H),6.65 (d, J=2.0 Hz, 1H), 5.02-4.96 (m, 1H), 3.95-3.90 (m, 2H), 3.76-3.73(m, 2H).

Example 41 3-(4-Chloro-4′-fluoro-3′-methyl-biphenyl-2-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₆H₁₅ClFNO, 291.1. m/z found, 292.2 [M+H]⁺.¹H NMR (CDCl₃): 7.35-7.29 (m, 2H), 7.24 (d, J=8.2 Hz, 1H), 7.09-7.00 (m,2H), 6.63 (d, J=2.0 Hz, 1H), 5.07-4.90 (m, 1H), 4.03-3.86 (m, 2H),3.84-3.67 (m, 2H), 2.33 (s, 3H).

Example 42 3-(4-Chloro-3′,4′-dimethyl-biphenyl-2-yloxy)-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO, 287.1. m/z found, 288.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.38-7.34 (m, 1H), 7.32-7.25 (m, 2H), 7.22-7.17 (m, 1H),7.03 (dd, J=8.2, 2.0 Hz, 1H), 6.63 (d, J=2.0 Hz, 1H), 4.10-3.62 (m, 1H),4.08-3.62 (m, 4H), 2.33 (s, 3H), 2.32 (s, 3H).

Example 43 (±)-3-(4-Methoxy-2′-methyl-biphenyl-3-yl)-pyrrolidine

Step A: Preparation of2,2,2-Trifluoro-1-[3-(2-methoxy-phenyl)-pyrrolidin-1-yl]-ethanone

To 3-(2-Methoxy-phenyl)-pyrrolidine hydrochloride (5.4 g, 25.3 mmol) inCH₂Cl₂ (125 mL) at 0° C. was added Et₃N (7.4 mL, 53.1 mmol) and TFAA(5.8 g, 3.9 mL, 27.8 mmol). After 15 h, H₂O was added and the mixtureextracted with CH₂Cl₂ (2×). The combined organics were dried. Silica gelchromatography (5-30% EtOAc in hexanes) gave 7.56 of the title compound.

Step B: Preparation of1-[3-(5-Bromo-2-methoxy-phenyl)-pyrrolidin-1-yl]-2,2,2-trifluoro-ethanone

To the title compound of Step A (2.75 g, 10.1 mmol) and NaBr (4.2 g, 41mmol) in acetone (50 mL)/H₂O (50 mL) at 0° C. was added Oxone (6.2 g,10.1 mmol) portionwise over 1 h. After 3 h, the ice bath was removed andthe reaction allowed to warm to rt. Then 5 wt % Na₂S₂O₅ (aq.) was addedand the mixture extracted with EtOAc (2×). The combined organics werewashed with brine and dried to give 3.95 g (>98%) of the title compound.¹H NMR (CDCl₃): 7.35 (dd, J=8.7, 3.8, 2.5 Hz, 1H), 7.25 (dd, J=5.5, 2.7Hz, 1H), 6.77 (dd, J=8.7, 4.5 Hz, 1H), 4.13-4.06 (m, 1H), 3.94-3.82 (m,4H), 3.75-3.57 (m, 2H), 3.51-3.41 (m, 1H), 2.37-2.05 (m, 2H).

Step C: Preparation of2,2,2-Trifluoro-1-[3-(4-methoxy-2′-methyl-biphenyl-3-yl)-pyrrolidin-1-yl]-ethanone

Prepared according to Example 38 Step B using 2-methylphenylboronicacid.

Step D: Preparation of(±)-3-(4-Methoxy-2′-methyl-biphenyl-3-yl)-pyrrolidine

Prepared according to general procedure 2 from the title compound ofStep C. MS (ESI): mass calcd. for C₁₈H₂₁NO, 267.2. m/z found, 268.3[M+H]⁺. ¹H NMR (CDCl₃): 7.33-7.12 (m, 6H), 6.96-6.85 (m, 1H), 5.26-4.84(br m, 1H), 3.79-3.56 (m, 1H), 3.57-3.38 (m, 1H), 3.38-3.18 (m, 1H),3.05-2.88 (m, 1H), 2.30 (s, 3H), 2.25-2.11 (m, 1H), 2.07-1.85 (m, 1H).

Unless otherwise specified the compounds in Examples 44-49 were preparedsimilar to Example 43 using the appropriate arylboronic acid.

Example 44(±)-3-(3′-Fluoro-4-methoxy-2′-methyl-biphenyl-3-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₂₀FNO, 285.2. m/z found, 286.3 [M+H]⁺. ¹HNMR (CDCl₃): 7.45-7.38 (m, 0.5H), 7.35-7.26 (m, 1.5H), 7.21-7.08 (m,2.5H), 7.04-6.95 (m, 1.5H), 6.93-6.86 (m, 1H), 3.87 (s, 3H), 3.65-3.48(m, 1H), 3.39-3.26 (m, 1H), 3.22-3.10 (m, 1H), 3.10-2.97 (m, 1H),2.93-2.80 (m, 1H), 2.23-2.09 (m, 3H), 1.96-1.77 (m, 1H).

Example 45 (±)-3-(2′,3′-Difluoro-4-methoxy-biphenyl-3-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₇F₂NO, 289.1. m/z found, 290.3[M+H]⁺. ¹HNMR (CDCl₃): 7.43-7.33 (m, 2H), 7.19-7.02 (m, 3H), 6.93 (d, J=9.1 Hz,1H), 3.87 (s, 3H), 3.65-3.51 (m, 1H), 3.42-3.30 (m, 1H), 3.27-3.13 (m,2H), 3.13-3.00 (m, 1H), 2.98-2.87 (m, 1H), 2.27-2.12 (m, 1H), 2.02-1.84(m, 1H).

Example 46(±)-3-(4-Methoxy-3′-trifluoromethyl-biphenyl-3-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₁₈F₃NO, 321.1. m/z found, 322.3 [M+H]⁺. ¹HNMR (CDCl₃): 7.74 (d, J=7.9 Hz, 1H), 7.55 (dd, J=7.5, 7.0 Hz, 1H), 7.45(dd, J=7.7, 7.5 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.27-7.22 (m, 1H),7.20-7.14 (m, 2H), 6.95-6.87 (m, 1H), 3.89 (s, 3H), 3.65-3.51 (m, 1H),3.40-3.26 (m, 1H), 3.22-3.10 (m, 1H), 3.09-2.99 (m, 1H), 2.93-2.80 (m,1H), 2.25-2.11 (m, 1H), 1.98-1.78 (m, 1H).

Example 47(±)-3-(4-Methoxy-2′-trifluoromethyl-biphenyl-3-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₁₈F₃NO, 321.1. m/z found, 322.3 [M+H]⁺. ¹HNMR (CDCl₃): 7.74 (d, J=7.9 Hz, 1H), 7.56 (dd, J=8.0, 7.5 Hz, 1H), 7.45(dd, J=7.7, 7.5 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.29-7.22 (m, 1H),7.19-7.13 (m, 2h), 6.94-6.87 (m, 1H), 3.89 (5, 3H), 3.63-3.53 (m, 1H),3.37-3.27 (m, 1H), 3.21-3.10 (m, 1H), 3.09-2.98 (m, 1H), 2.92-2.82 (m,1H), 2.24-2.11 (m, 1H), 1.94-1.80 (m, 1H).

Example 48(±)-3-(4-Methoxy-2′-trifluoromethoxy-biphenyl-3-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₁₈F₃NO₂, 337.1. m/z found, 338.3 [M+H]⁺.¹H NMR (CDCl₃): 7.45-7.35 (m, 1.5H), 7.34-7.25 (m, 3.5H), 7.18-7.05 (m,1H), 6.97-6.89 (m, 1H), 3.87 (s, 3H), 3.65-3.51 (m, 1H), 3.38-3.25 (m,1H), 3.23-3.11 (m, 1H), 3.09-2.97 (m, 1H), 2.93-2.81 (m, 1H), 2.26-2.09(m, 1H), 1.98-1.77 (m, 1H).

Example 49 (±)-3-(4-Methoxy-biphenyl-3-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₉NO, 253.2. m/z found, 254.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.62-7.52 (m, 2H), 7.48-7.39 (m, 4H), 7.36-7.27 (m, 1H),6.95 (d, J=8.7 Hz, 1H), 3.89 (s, 3H), 3.68-3.51 (m, 1H), 3.49-3.31 (m,1H), 3.30-3.17 (m, 1H), 3.16-3.06 (m, 1H), 3.05-2.91 (m, 1H), 2.71-2.39(br m, 1H), 2.31-2.10 (m, 1H), 2.05-1.83 (m, 1H).

Example 50 (±)-3-(4-Methoxy-biphenyl-3-yl)-1-methyl-pyrrolidine

Prepared from the title compound of Example 49 using general procedure3. MS (ESI): mass calcd. for C₁₈H₂₁NO, 267.2. m/z found, 268.3 [M+H]⁺.¹H NMR (CDCl₃): 7.59-7.50 (m, 3H), 7.45-7.36 (m, 3H), 7.33-7.26 (m, 1H),6.91 (d, J=8.4 Hz, 1H), 3.86 (s, 3H), 3.84-3.73 (m, 1H), 3.01 (dd,J=8.6, 8.5 Hz, 1H), 2.87-2.76 (m, 1H), 2.69-2.59 (m, 1H), 2.54 (dd,J=8.8, 8.4 Hz, 1H), 2.41 (s, 3H), 2.38-2.25 (m, 1H), 2.00-1.87 (m, 1H).

Example 51 (±)-3-Biphenyl-2-yl-pyrrolidine

Step A: Preparation of2,2,2-Trifluoro-1-[3-(2-hydroxy-phenyl)-pyrrolidin-1-yl]-ethanone

To the title compound of Example 43 Step A (1.2 g, 4.4 mmol) in CH₂Cl₂(15 mL) at 0° C. was added BBr₃ (1M in CH₂Cl₂, 9.8 mL, 9.8 mmol). Afterwarming to rt and allowing to stir for 18 h, sat'd NaHCO₃ (aq.) wasadded slowly. The reaction was then extracted with CH₂Cl₂. The combinedorganic layers were dried and used in the next step without furtherpurification. MS (ESI): mass calcd. for C₁₂H₁₂F₃NO₂, 259.2. m/z found,260.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.22-7.11 (m, 2H), 6.97-6.88 (m, 1H),6.87-6.77 (m, 1H), 4.26-4.14 (m, 1H), 4.04-3.94 (m, 0.5H), 3.93-3.84 (m,0.5H), 3.82-3.71 (m, 1H), 3.70-3.53 (m, 2H), 2.44-2.26 (m, 1.5H),2.25-2.13 (m, 0.5H).

Step B: Preparation of Trifluoro-methanesulfonic acid2-[1-(2,2,2-trifluoro-acetyl)-pyrrolidin-3-yl]-phenyl ester

Prepared according to Example 38 Step A using the title compound fromStep A. MS (ESI): mass calcd. for C₁₃H₁₁F₆NO₄S, 391.2. m/z found, 392.1[M+H]⁺. ¹H NMR (CDCl₃): 7.50-7.37 (m, 3H), 7.36-7.30 (m, 1H), 4.18 (dd,J=10.6, 7.9 Hz, 0.5H), 4.10 (dd, J=12.5, 7.8 Hz, 0.5H), 3.97 (dd,J=10.9, 10.8 Hz, 0.5H), 3.94-3.87 (m, 0.5H), 3.86-3.66 (m, 2H),3.65-3.56 (m, 1H), 2.55-2.46 (m, 0.5H), 2.45-2.37 (m, 0.5H), 2.23-2.13(m, 0.5H), 2.12-2.02 (m, 0.5H).

Step C: Preparation of(±)-1-(3-Biphenyl-2-yl-pyrrolidin-1-yl)-2,2,2-trifluoro-ethanone

To a nitrogen flushed flask containing the title compound of Step C (75mg, 0.19 mmol), phenylboronic acid (35 mg, 0.29 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (7 mg, 5 mol %), dppf (5 mg, 5 mol %) and K₃PO₄ (60mg, 0.3 mmol) was added dioxane (5 mL). The reaction was heated atreflux for 18 h. After cooling to rt, the crude reaction mixture wasfiltered through a 1″×½″ silica gel plug and the plug was rinsed withDCM. The filtrate was concentrated and purified by RP HPLC to providethe title compound (34 mg, 56%). MS (ESI): mass calcd. for C₁₈H₁₆F₃NO,319.1. m/z found, 320.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.52-7.37 (m, 4H),7.37-7.22 (m, 5H), 3.98-3.81 (m, 2H), 3.62-3.41 (m, 3H), 2.28-1.98 (m,2H).

Step E: Preparation of (±)-3-Biphenyl-2-yl-pyrrolidine

Prepared according to general procedure 2 from the title compound ofStep C. ¹H NMR (CDCl₃): 7.47-7.39 (m, 3H), 7.39-7.36 (m, 2H), 7.33-7.29(m, 2H), 7.27-7.20 (m, 2H), 3.38-3.10 (m, 3H), 3.08-2.77 (m, 2H),2.75-2.36 (m, 1H), 2.21-1.99 (m, 1H), 1.95-1.75 (m, 1H).

Unless otherwise specified the compounds in Examples 52-67 were preparedsimilar to Example 51 using the appropriate arylboronic acid.

Example 52 (±)-3-(3′-Methyl-biphenyl-2-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₉N, 237.2. m/z found, 238.3 [M+H]⁺. ¹HNMR (CDCl₃): 7.44-7.38 (m, 1H), 7.37-7.33 (m, 1H), 7.33-7.27 (m, 1H),7.26-7.16 (m, 3H), 7.14-7.06 (m, 2H), 3.44-3.10 (m, 2H), 3.09-2.73 (m,2H), 2.42 (s, 3H), 2.33-1.99 (m, 3H), 1.94-1.73 (m, 1H).

Example 53 (±)-1-Methyl-3-(3′-methyl-biphenyl-2-yl)-pyrrolidine

Prepared according to general procedure 3 using Example 52. MS (ESI):mass calcd. for C₁₈H₂₁N, 251.2. m/z found, 252.3 [M+H]⁺. ¹H NMR (CDCl₃):7.56 (d, J=7.9 Hz, 1H), 7.37 (dt, J=1.6, 7.6 Hz, 1H), 7.32-7.27 (m, 1H),7.25-7.14 (m, 3H), 7.12-7.05 (m, 2H), 3.55-3.43 (m, 1H), 2.81 (dd,J=9.0, 8.6 Hz, 1H), 2.77-2.63 (m, 2H), 2.58 (dd, J=7.4, 7.3 Hz, 1H),2.41 (s, 3H), 2.39 (s, 3H), 2.42-2.14 (m, 1H), 1.95-1.84 (m, 1H).

Example 54 (±)-3-(4′-Methyl-biphenyl-2-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₉N, 237.2. m/z found, 238.3 [M+H]⁺. ¹HNMR (CDCl₃): 7.44-7.39 (m, 1H), 7.38-7.32 (m, 1H), 7.27-7.15 (m, 6H),3.41-3.13 (m, 2H), 3.09-2.82 (m, 2H), 2.81-2.55 (m, 2H), 2.42 (s, 3H),2.21-2.02 (m, 1H), 1.97-1.82 (m, 1H).

Example 55 (±)-1-Methyl-3-(4′-methyl-biphenyl-2-yl)-pyrrolidine

Prepared according to general procedure 3 using the title compound ofExample 54. MS (ESI): mass calcd. for C₁₈H₂₁N, 251.2. m/z found, 252.3[M+H]⁺. ¹H NMR (CDCl₃): 7.56 (d, J=8.7 Hz, 1H), 7.37 (dt, J=1.7, 7.2 Hz,1H), 7.25-7.16 (m, 6H), 3.55-3.44 (m, 1H), 2.80 (dd, J=9.0, 8.5 Hz, 1H),2.75-2.68 (m, 1H), 2.68-2.61 (m, 1H), 2.61-2.55 (m, 1H), 2.42 (s, 3H),2.38 (s, 3H), 2.25-2.13 (m, 1H), 1.95-1.85 (m, 1H).

Example 56 3-(4′-Chloro-biphenyl-2-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₆H₁₆ClN, 257.10. m/z found, 258.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.44-7.30 (m, 4H), 7.25-7.19 (m, 3H), 7.16 (dd, J=7.6, 1.2Hz, 1H), 3.28-3.10 (m, 3H), 3.01-2.96 (m, 1H), 2.90-2.77 (m, 1H), 2.50(s, 1H), 1.87-1.80 (m, 1H).

Example 57 (±)-3-(3′,4′-Dimethyl-biphenyl-2-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₂₁N, 251.2. m/z found, 252.3 [M+H]⁺. ¹HNMR (CDCl₃): 7.45-7.38 (m, 1H), 7.37-7.30 (m, 1H), 7.26-7.15 (m, 3H),7.12-7.07 (m, 1H), 7.06-6.91 (m, 1H), 3.40-3.11 (m, 3H), 3.09-2.76 (m,2H), 2.34 (s, 3H), 2.33 (s, 3H), 2.27-2.05 (m, 2H), 1.93-1.80 (m, 1H).

Example 58 (±)-3-(3′,4′-Dimethyl-biphenyl-2-yl)-1-methyl-pyrrolidine

Prepared from general procedure 3 using the title compound of Example57. MS (ESI): mass calcd. for C₁₉H₂₃N, 265.2. m/z found, 266.3 [M+H]⁺.¹H NMR (CDCl₃): 7.55 (d, J=8.0 Hz, 1H), 7.35 (dt, J=1.8, 7.1 Hz, 1H),7.22 (dd, J=7.6, 1.3 Hz, 1H), 7.20 (dd, J=3.6, 1.2 Hz, 1H), 7.17 (d,J=8.0 Hz, 1H), 7.06 (s, 1H), 3.55-3.45 (m, 1H), 2.80 (dd, J=9.0, 8.5 Hz,1H), 2.75-2.68 (m, 1H), 2.58 (dd, J=9.2, 7.3 Hz, 1H), 2.39 (s, 3H), 2.32(s, 3H), 2.31 (s, 3H), 2.25-2.14 (m, 1H), 1.95-1.84 (m, 1H).

Example 59 (±)-3-(2′-Methyl-biphenyl-2-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₂₁N, 237.2. m/z found, 238.3 [M+H]⁺. ¹HNMR (CDCl₃): 7.46-7.32 (m, 1.5H), 7.29-7.18 (m, 5H), 7.15-7.05 (m,1.5H), 3.22-3.07 (m, 1.5H), 3.05-2.87 (m, 2H), 2.84-2.69 (m, 0.5H),2.62-2.32 (m, 1.5H), 2.08 (s, 1.5H), 2.06 (s, 1.5H), 2.05-2.01 (m, 1H),1.95-1.82 (m, 0.5H), 1.83-1.65 (m, 0.5H).

Example 60 (±)-1-Methyl-3-(2′-methyl-biphenyl-2-yl)-pyrrolidine

Prepared according to general procedure 3 using Example 59. MS (ESI):mass calcd. for C₁₈H₂₁N, 251.2. m/z found, 252.3 [M+H]⁺. ¹H NMR (CDCl₃):7.56 (d, J=7.9 Hz, 0.5H), 7.53 (d, J=7.9 Hz, 0.5H), 7.37 (dd, J=7.9, 7.2Hz, 1H), 7.27-7.18 (m, 4H), 7.11-7.06 (m, 2H), 3.26-3.08 (m, 1H),2.83-2.51 (m, 3.5H), 2.46-2.38 (m, 0.5H), 2.37 (s, 3H), 2.34 (s, 3H),2.18-2.06 (m, 1H), 2.06 (s, 1.5H), 2.05 (s, 1.5H), 1.96-1.85 (m, 0.5H),1.84-1.74 (m, 0.5H).

Example 61 (±)-3-(2′-Methoxy-biphenyl-2-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₉NO, 253.2. m/z found, 254.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.45-7.32 (m, 3H), 7.27-7.21 (m, 1H), 7.21-7.11 (m, 2H),7.05-6.99 (m, 1H), 6.99-6.92 (m, 1H), 3.75 (s, 1.5H), 3.74 (s, 1.5H),3.36-3.04 (m, 3H), 3.04-2.87 (m, 2H), 2.87-2.63 (m, 1H), 2.21-2.08 (m,0.5H), 2.08-1.86 (m, 1H), 1.83-1.67 (m, 0.5H).

Example 62 (±)-3-(2′-Methoxy-biphenyl-2-yl)-1-methyl-pyrrolidine

Prepared according to general procedure 3 using the title compound ofExample 61. MS (ESI): mass calcd. for C₁₈H₂₁NO, 267.2. m/z found, 268.3[M+H]⁺. ¹H NMR (CD₃OD/CDCl₃): 7.42-7.35 (m, 1H), 7.32-7.21 (m, 2H),7.20-7.11 (m, 1H), 7.08-7.00 (m, 2H), 6.96-6.89 (m, 1H), 6.89 (d, J=8.3Hz, 1H), 3.65 (s, 3H), 3.30-3.13 (m, 1.5H), 2.88-2.77 (m, 0.5H),2.78-2.64 (m, 1H), 2.61-2.47 (m, 2H), 2.28 (s, 1.5H), 2.24 (s, 1.5H),2.19-2.05 (m, 0.5H), 2.01-1.82 (m, 1H), 1.79-1.64 (m, 0.5H).

Example 63 (±)-3-(2′-Methoxy-5′-methyl-biphenyl-2-yl)-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₂₁NO, 267.2. m/z found, 268.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.39-7.29 (m, 2H), 7.24-7.18 (m, 1H), 7.16-7.10 (m, 2H),7.00-6.93 (m, 1H), 6.88-6.83 (m, 1H), 3.75-3.68 (m, 3H), 3.37-3.05 (m,3H), 3.04-2.65 (m, 2H), 2.37-2.31 (m, 3H), 2.22-1.69 (m, 2H).

Example 64(±)-3-(2′-Methoxy-5′-methyl-biphenyl-2-yl)-1-methyl-pyrrolidine

Prepared according to general procedure 3 using the title compound ofExample 63. MS (ESI): mass calcd. for C₁₉H₂₃NO, 281.2. m/z found, 282.3[M+H]⁺. ¹H NMR (CDCl₃): 7.24-7.17 (m, 1H), 7.15-7.08 (m, 2H), 6.92 (dd,J=7.3, 2.2 Hz, 1H), 6.82 (dd, J=8.3, 2.3 Hz, 1H), 3.69 (s, 3H),3.36-3.17 (m, 1H), 2.88-2.49 (m, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.30(s, 3H), 2.27-2.13 (m, 1H), 2.12-2.00 (m, 1H), 2.00-1.84 (m, 1H),1.84-1.68 (m, 1H).

Example 65 (±)-3-(4,3′-Dichloro-biphenyl-2-yl)-pyrrolidine

Step A: Preparation of1-[3-(5-Chloro-2-methoxy-phenyl)-pyrrolidin-1-yl]-2,2,2-trifluoro-ethanone

To the title compound of Example 43 Step A (1.61 g, 5.9 mmol) in MeCN(60 mL) at 0° C. was added oxone (3.6 g, 5.9 mmol) slowly such that theinternal temperature of the reaction did not exceed 5° C. over 2 h. Thereaction was then placed in a 4° C. freezer for 18 h, then allowed towarm to rt. After an additional 8 h at rt, 10% sodium bisulfite (aq.)was added and the mixture extracted with CH₂Cl₂ (2×). The combinedorganic layers were dried and purified. MS (ESI): mass calcd. forC₁₃H₁₃ClF₃NO₂, 307.1. m/z found, 308.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.26-7.19(m, 1H), 7.15-7.10 (m, 1H), 6.83 (dd, J=8.7, 4.7 Hz, 1H), 4.18-4.06 (m,1H), 3.98-3.88 (m, 1H), 3.86 (s, 1.5H), 3.84 (s, 1.5H), 3.78-3.68 (m,1H), 3.67-3.57 (m, 1H), 3.56-3.41 (m, 1H).

Step B: Preparation of1-[3-(5-Chloro-2-hydroxy-phenyl)-pyrrolidin-1-yl]-2,2,2-trifluoro-ethanone

Prepared according to Example 51 Step A from the title compound of StepA. MS (ESI): mass calcd. for C₁₂H₁₁ClF₃NO₂, 293.7; m/z found, 294.2[M+H]⁺. ¹H NMR (CDCl₃): 7.38-7.17 (m, 2H), 7.10-6.84 (m, 1H), 4.22-4.00(m, 1H), 3.99-3.34 (m, 4H), 2.68-2.25 (m, 2H).

Step C: Preparation of Trifluoro-methanesulfonic acid4-chloro-2-[1-(2,2,2-trifluoro-acetyl)-pyrrolidin-3-yl]-phenyl ester

Prepared according to Example 38 Step A using the title compound of StepB. MS (ESI): mass calcd. for C₁₃H₁₀ClF₆NO₄S, 425.7. m/z found, 426.1[M+H]⁺. ¹H NMR (CDCl₃): 7.41-7.35 (m, 2H), 7.30-7.24 (m, 1H), 4.19 (dd,J=10.4, 7.9 Hz, 0.5H), 4.12 (dd, J=12.5, 7.9 Hz, 0.5H), 4.00 (dd, J=9.6,8.3 Hz, 0.5H), 3.94 (ddd, J=12.1, 8.5, 2.8 Hz, 0.5H), 3.82-3.73 (m, 1H),3.72-3.64 (m, 1H), 3.61-3.51 (m, 1H), 2.55-2.38 (m, 0.5H), 2.22-2.01 (m,1H).

Step D: Preparation of1-[3-(4,3′-Dichloro-biphenyl-2-yl)-pyrrolidin-1-yl]-2,2,2-trifluoro-ethanone

Prepared according to Example 51 Step C using the title compound of StepC. MS (ESI): mass calcd. for C₁₈H₁₄Cl₂F₃NO, 387.0; m/z found, 388.1[M+H]⁺. ¹H NMR (CDCl₃): 7.47-7.34 (m, 3H), 7.33-7.23 (m, 2H), 7.20-7.08(m, 2H), 4.01-3.92 (m, 0.5H), 3.91-3.80 (m, 1.5H), 3.63-3.54 (m, 0.5H),3.53-3.43 (m, 2H), 3.42-3.31 (m, 0.5H), 2.32-2.11 (m, 1.5H), 2.10-1.97(m, 0.5H).

Step E. Preparation of 3-(4,3′-Dichloro-biphenyl-2-yl)-pyrrolidine

Prepared according to general procedure 3 using the title compound fromStep D. MS (ESI): mass calcd. for C₁₆H₁₅O₂N, 291.1. m/z found, 292.1[M+H]⁺. ¹H NMR (CDCl₃): 7.44-7.41 (m, 1H), 7.37-7.32 (m, 2H), 7.27-7.19(m, 2H), 7.17-7.07 (m, 2H), 4.65-3.95 (br m, 1H), 3.70-3.45 (m, 1H),3.42-3.14 (m, 3H), 2.22-2.04 (m, 1.5H), 2.00-1.82 (m, 1.5H).

Example 66(±)-3-(4-Chloro-4′-fluoro-3′-methyl-biphenyl-2-yl)-pyrrolidine

Prepared according to Example 65 using 3-methyl-4-fluorophenylboronicacid. MS (ESI): mass calcd. for C₁₇H₁₇ClFN, 289.1. m/z found, 290.2[M+H]⁺. ¹H NMR (CDCl₃): 7.38 (d, J=2.1 Hz, 1H), 7.19 (dd, J=8.2, 2.2 Hz,1H), 7.10 (d, J=8.2 Hz, 1H), 7.08-6.98 (m, 3H), 3.32-3.12 (m, 3H),3.09-2.73 (m, 3H), 2.32 (s, 3H), 2.17-2.03 (m, 1H), 1.89-1.74 (m, 1H).

Example 67 (±)-3-(4-Chloro-3′,4′-dimethyl-biphenyl-2-yl)-pyrrolidine

Prepared according to Example 65 using 3,4-dimethylphenylboronic acid.MS (ESI): mass calcd. for C₁₈H₂₀ClN, 285.1. m/z found, 286.3 [M+H]⁺. ¹HNMR (CDCl₃): 7.38 (d, J=2.2 Hz, 1H), 7.20 (dd, J=8.3, 2.1 Hz, 1H), 7.18(d, J=8.2 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.04 (s, 1H), 7.00 (dd,J=7.6, 1.5 Hz, 1H), 3.38-3.10 (m, 3H), 3.07-2.72 (m, 3H), 2.33 (s, 3H),2.32 (s, 3H), 2.21-2.02 (m, 1H), 1.89-1.74 (m, 1H).

The compounds in Examples 68-69 were prepared similar to Example 1 using4-(5-bromo-2-methoxy-phenoxy)-piperidine-1-carboxylic acid tert-butylester and the appropriately substituted phenylboronic acid.

Example 68 4-(4-Methoxy-biphenyl-3-yloxy)-piperidine

MS (ESI): mass calcd. for C₁₈H₂₁NO₂, 283.2. m/z found, 284.3 [M+H]⁺. ¹HNMR (CD₃OD/CDCl₃): 7.53 (d, J=7.9 Hz, 1H), 7.46-7.37 (m, 2H), 7.31 (dd,J=7.4, 7.3 Hz, 2H), 7.24-7.13 (m, 2H), 6.99 (d, J=8.3 Hz, 1H), 4.46-3.34(m, 1H), 3.90 (s, 3H), 3.24-3.08 (m, 2H), 2.79-2.63 (m, 2H), 2.14-1.97(m, 2H), 1.83-1.68 (m, 2H).

Example 69 4-(4-Methoxy-2′-trifluoromethyl-biphenyl-3-yloxy)-piperidine

MS (ESI): mass calcd. for C₁₉H₂₀F₃NO₂, 351.1. m/z found, 352.3 [M+H]⁺.¹H NMR (CDCl₃): 7.73 (d, J=7.8 Hz, 1H), 7.53 (dd, J=7.6, 7.5 Hz, 1H),7.43 (dd, J=7.6, 7.6 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 6.94-6.86 (m, 3H),4.37-4.23 (m, 1H), 3.92 (s, 3H), 3.24-3.10 (m, 2H), 2.74-2.61 (m, 2H),2.11-1.95 (m, 2H), 1.76-1.61 (m, 2H).

Biological Assays

r5-HT₇ binding assay

Receptor binding was performed using membrane fractions prepared fromthe HEK-293 cell line recombinantly expressing rat 5-HT₇ receptors (NCBIaccession NM_(—)022938). Compound affinity for the rat 5-HT₇ receptorsubtype was evaluated by competitive radioligand binding assays using5-carboxamido[³H]tryptamine ([³H]5-CT) (Amersham Biosciences, cat.90000403) detection. HitHunter™ cAMP assays are in-vitro basedcompetitive immunoassays. The assay was performed on the HEK-293 cellline stably transfected with r5-HT₇ receptor. Cells were pre-incubatedwith test compounds for 10 minutes. For agonistic testing, theconcentration of test compound that produced a half-maximal response isrepresented by the EC₅₀ value. Compounds were assayed in their free formor as salts, as indicated in the Examples section above.

TABLE 1 Binding Affinities and Functional Activity Ex 5HT₇ Ki (nM) pEC501 3.79 6.7 2 21.00 ND 3 33.88 ND 4 11.00 6.2 5 19.00 5.8 6 8.20 ND 710.00 ND 8 13.49 6.1 9 50.00 ND 10 112.00 ND 11 759.98 ND 12 770.02 ND13 1000.00 ND 14 249.98 ND 15 120.01 ND 16 114.00 ND 17 4.42 6.1 18532.97 ND 19 299.99 ND 20 25.50 ND 21 34.64 ND 22 751.97 ND 23 67.00 ND24 8.89 ND 25 10.49 ND 26 15.49 ND 27 410.02 ND 28 127.00 ND 29 10000.00ND 30 508.04 ND 31 10000.00 ND 32 454.05 ND 33 525.05 ND 34 666.96 ND 35754.92 ND 36 10000.00 ND 37 2267.25 ND 38 189.02 ND 39 ND ND 40 ND ND 41470.00 ND 42 209.99 ND 43 5.46 ND 44 19.00 ND 45 52.00 ND 46 117.00 ND47 7.98 ND 48 19.77 ND 49 129.99 ND 50 150.00 ND 51 120.01 ND 52 80.24ND 53 310.03 ND 54 120.01 ND 55 430.03 ND 56 180.01 ND 57 55.94 ND 58155.02 ND 59 209.99 ND 60 329.99 ND 61 299.99 ND 62 729.96 ND 63 1699.81ND 64 ND ND 65 129.99 ND 66 380.01 ND 67 120.01 ND 68 1482.86 ND 6959.01 ND *ND symbolizes not determined.

While the invention has been illustrated by reference to exemplary andpreferred embodiments, it will be understood that the invention isintended not to be limited by the foregoing detailed description, but tobe defined by the appended claims as properly construed under principlesof patent law.

1.-22. (canceled)
 23. A method of treating a subject suffering from ordiagnosed with a disease, disorder, or condition mediated by 5HT₇activity, comprising administering to the subject an effective amount ofat least one compound of Formulae (I) or (II):

wherein R¹ is —H, —C₁₋₄alkyl, or C₃₋₆cycloalkyl; m is 1 or 2, n is 1 or2, with the proviso that if m is 2, then n is not 1; L is absent or O;R² is —H, halo, —CN, —CF₃, —OC₀₋₄alkylCF₃, —OC₁₋₄alkyl,—C₃₋₆cycloalkoxy, —OCH₂C₃₋₆cycloalkyl, or —C(O)N(R_(a))₂; each R_(a) isindividually —H or —C₁₋₄alkyl; R³ is —H or —C₁₋₄alkyl; o is 0, 1, or 2;and each R⁴ substituent is independently —H, halo, —OCF₃, —CF₃, —CN,—C₁₋₄alkyl, or —OC₁₋₄alkyl; or a pharmaceutically acceptable salt of acompound of Formulae (I) or (II), a pharmaceutically acceptable prodrugof a compound of Formulae (I) or (II), or a pharmaceutically activemetabolite of a compound of Formulae (I) or (II).
 24. A method accordingto claim 23, wherein the disease, disorder, or condition is selectedfrom the group consisting of: sleep disorders, depression/anxiety,generalized anxiety disorder, schizophrenia, bipolar disorders,cognitive disorders, mild cognitive impairment, Alzheimer's disease,Parkinson's disease, psychotic disorders, phobic disorders,obsessive-compulsive disorder, mood disorders, post-traumatic stress,migraine, pain, eating disorders, obesity, sexual dysfunction, metabolicdisturbances, hormonal imbalance, hot flushes associated with menopause,alcohol abuse, drug abuse, drug addiction, alcohol addiction, nausea,inflammation, centrally mediated hypertension, sleep/wake disturbances,jetlag, and circadian rhythm abnormalities.
 25. A method of treating asubject suffering from or diagnosed with a disease, disorder, orcondition selected from the group consisting of: sleep disorders,depression/anxiety, generalized anxiety disorder, schizophrenia, bipolardisorders, cognitive disorders, mild cognitive impairment, Alzheimer'sdisease, Parkinson's disease, psychotic disorders, phobic disorders,obsessive-compulsive disorder, mood disorders, post-traumatic stressdisorder, migraine, pain, eating disorders, obesity, sexual dysfunction,metabolic disturbances, hormonal imbalance, hot flushes associated withmenopause, alcohol abuse, drug abuse, drug addiction, alcohol addiction,nausea, inflammation, centrally mediated hypertension, sleep/wakedisturbances, jetlag, and circadian rhythm abnormalities, comprisingadministering to the subject an effective amount of at least onecompound of Formulae (I) or (II):

wherein R¹ is —H, —C₁₋₄alkyl, or C₃₋₆cycloalkyl; m is 1 or 2, n is 1 or2, with the proviso that if m is 2, then n is not 1; L is absent or O;R² is —H, halo, —CN, —CF₃, —OC₀₋₄alkylCF₃, —OC₁₋₄alkyl,—C₃₋₆cycloalkoxy, —OCH₂C₃₋₆cycloalkyl, or —C(O)N(R_(a))₂; each R_(a) isindividually —H or —C₁₋₄alkyl; R³ is —H or —C₁₋₄alkyl; o is 0, 1, or 2;and each R⁴ substituent is independently —H, halo, —OCF₃, —CF₃, —CN,—C₁₋₄alkyl, or —OC₁₋₄alkyl; or a pharmaceutically acceptable salt of acompound of Formulae (I) or (II), a pharmaceutically acceptable prodrugof a compound of Formulae (I) or (II), or a pharmaceutically activemetabolite of a compound of Formulae (I) or (II).
 26. A method accordingto claim 25, wherein the disease, disorder, or condition is selectedfrom the group consisting of: sleep disorders, depression/anxiety,generalized anxiety disorder, schizophrenia, bipolar disorders,cognitive disorders, mild cognitive impairment, Alzheimer's disease,Parkinson's disease, psychotic disorders, phobic disorders,obsessive-compulsive disorder, mood disorders, post-traumatic stressdisorder, pain, alcohol abuse, drug abuse, drug addiction, and alcoholaddiction.
 27. A method according to claim 25, wherein the disease,disorder, or condition is selected from the group consisting of:depression/anxiety, generalized anxiety disorder, schizophrenia, bipolardisorders, psychotic disorders, phobic disorders, obsessive-compulsivedisorder, and mood disorders.
 28. A method according to claim 25,wherein the disease, disorder, or condition is selected from the groupconsisting of: alcohol abuse, drug abuse, drug addiction, and alcoholaddiction.
 29. A method according to claim 25, wherein the disease,disorder, or condition is Alzheimer's disease.
 30. A method according toclaim 25, wherein the disease, disorder, or condition is post-traumaticstress disorder.
 31. A method according to claim 25, wherein thedisease, disorder, or condition is drug addiction.
 32. A methodaccording to claim 25, wherein the disease, disorder, or condition isalcohol addiction.
 33. A method according to claim 25, wherein thedisease, disorder, or condition is pain.
 34. A method according to claim25, wherein the disease, disorder, or condition is depression/anxiety.